WO2011139832A2

WO2011139832A2 - Method for treating mycobacterial infections

Info

Publication number: WO2011139832A2
Application number: PCT/US2011/034319
Authority: WO
Inventors: Joseph A. Devito; Joyce A. Sutcliffe
Original assignee: Rib-X Pharmaceuticals, Inc.
Priority date: 2010-04-28
Filing date: 2011-04-28
Publication date: 2011-11-10
Also published as: WO2011139832A3

Abstract

The present invention relates to methods for treating mycobacterial infections, for example infections caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria, using a safe and effective amount of an antibiotic compound.

Description

METHOD FOR TREATING MYCOBACTERIAL INFECTIONS

RELATED APPLICATIONS

This application claims priority and benefit of U.S. provisional application no.

61/328,775, filed April 28, 2010. The entire contents of the application are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to methods for treating mycobacterial infections, for example infections caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria, using a safe and effective amount of an antibiotic compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer.

BACKGROUND

Tuberculosis is a chronic, infectious disease caused by infection with Mycobacterium tuberculosis (M. tuberculosis). It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as a chronic inflammation of the lungs, resulting in fever and respiratory symptoms. If left untreated, significant morbidity and death can result. Current tuberculosis therapy is primarily based on four drugs, namely isoniazid, rifampin (also known as rifampicin), ethambutol, and pyrazinamide.

Although tuberculosis can generally be controlled, such treatment is not always sufficient to prevent the spread of the disease. Infected individuals may be asymptomatic, but contagious, for some time. Moreover, therapy usually requires long-term treatment (usually six to eight months), often using a combination of two or more drugs, many of which have undesirable toxicities and side effects. Because compliance with the treatment regimen is critical to success, patient behavior is difficult to monitor. Consequently, some patients do not complete the course of therapy, which can lead to ineffective treatment and the development of drug resistant M. tuberculosis strains. The increasing incidence of resistant and highly virulent strains of M. tuberculosis is presenting a further public health concern. The proportion of multidrug resistant mycobacteria isolates worldwide has increased from 29 percent in 2000 to 39% in 2004. The number of multidrug resistant tuberculosis cases rose 13.3% between 2003 and 2004 in the United States. In addition to tuberculosis, other diseases or conditions caused or mediated by other

Mycobacterium species are also a public health concern. For example, the nontuberculosis mycobacterial species Mycobacterium avium is responsible for causing often serious pulmonary infections, especially in immune-compromised patients such as those infected with HIV.

There is a need for effective compounds and methods for preventing and treating infectious disorders, such as tuberculosis and other infections mediated or caused by

mycobacterial microorganisms in humans and also in domestic mammals and livestock.

SUMMARY OF THE INVENTION

In addition, the present invention provides compositions useful in the present invention and provides the use of an antibiotic compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer in the manufacture of a medicament useful for treating mycobacterial infections, for example infections caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.

The foregoing and other aspects and embodiments of the present invention can be more fully understood by reference to the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods for treating mycobacterial infections, for example infections caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria, using a safe and effective amount of an antibiotic compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer. Such antibiotic compounds can include, for example, oxazolidinone antimicrobial compounds.

1. Definitions

The term "patient", as used herein, means the human or animal (in the case of an animal, more typically mammals and domestic animals) subject that would be considered to be in need of the methods of treating an infection caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.

As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "treating", as used herein, means to cure an already present infection caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria in a patient or subject.

The term "preventing", as used herein means, to completely or almost completely stop an infection caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria from occurring in a patient or subject, especially when the patient or subject is predisposed to such. Preventing can also include inhibiting, i.e. arresting the development of, an infection caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.

The term "reducing the risk of, as used herein, means to lower the likelihood or probability of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria from occurring, especially when the patient or subject is predisposed to such occurrence. As used herein, the term "pharmaceutically effective amount" refers to an amount of a compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer, or a combination of compounds or tautomers, of the present invention effective when administered alone or in combination with other active ingredients are useful to treat, prevent, or reduce the risk of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria. For example, a

pharmaceutically effective amount refers to an amount of the compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer present in a formulation or on a medical device given to a recipient patient or subject sufficient to elicit biological activity, for example, activity against an infection caused or mediated by

Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria. The combination of compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers optionally is a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds or tautomers thereof or a pharmaceutically acceptable salts or prodrugs of said compounds or tautomers when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds or tautomers thereof or a pharmaceutically acceptable salts or prodrugs of said compounds or tautomers. Synergy can be in terms of lower cytotoxicity, increased anti-proliferative and/or anti-infective effect, or some other beneficial effect of the combination compared with the individual components.

The term "prophylactically effective amount" means an effective amount of a compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer (or compounds or tautomers thereof or a pharmaceutically acceptable salts or prodrugs of said compounds or tautomers), of the present invention that is administered to prevent or reduce the risk of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria - in other words, an amount to needed provide a preventative or prophylactic effect. The terms "caused or mediated by" means that the infection has some connection, relation, or etiology to the designated microorganism, i.e. Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.

The terms "topical" and "topically" means that the antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers of the present invention can alternatively be administered or applied to the skin of the patient or subject, or to other non-internal organs or parts of the patient or subject including, for example, the hair, fur, feathers, scales, shells, eyes, and ears.

With respect to the antibiotic compounds or tautomers thereof or a pharmaceutically acceptable salts or prodrugs of said compounds or tautomers useful in the present invention, the following terms can be applicable, however, it should be kept in mind that more specific definitions are also given in the references referred to and incorporated by reference herein:

The chemical compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers described herein can have asymmetric centers.

Compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers of the present invention are described and can be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers of the present invention and intermediates made therein are, where appropriate, considered to be part of the present invention. All tautomers of shown or described compounds are also, where appropriate, considered to be part of the present invention. When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent can be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent can be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds or tautomers thereof wherein the parent compound or tautomer thereof is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound or tautomer thereof formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucohep tonic, gluconic, glutamic, N-methyl glutamic acid (i.e. the acid that would produce the D-gluconate salt), glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound or tautomer thereof that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds or tautomers thereof with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). For example, salts can include, but are not limited to, the hydrochloride and acetate salts of the aliphatic amine-containing, hydroxyl amine-containing, and imine-containing compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers of the present invention.

Additionally, the compounds or tautomers thereof or pharmaceutically salts or prodrugs of said compound or tautomers of the present invention, for example, the salts of the compounds or tautomers, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

The compounds or tautomers thereof or pharmaceutically acceptable salts of said compounds or tautomers of the present invention can also be prepared as prodrugs, for example pharmaceutically acceptable prodrugs. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds or tautomers thereof or pharmaceutically acceptable salts of said compounds or tautomers of the present invention can be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds or tautomers thereof or pharmaceutically acceptable salts of said compounds or tautomers, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound or tautomer thereof or a pharmaceutically acceptable salt thereof in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound or tautomer thereof or pharmaceutically acceptable salt of said compound or tautomer. Prodrugs include compounds or tautomers thereof or pharmaceutically acceptable salts of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds or tautomers thereof or pharmaceutically acceptable salts of the present invention.

"Stable compound" and "stable structure" are meant to indicate a compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer that is sufficiently robust to survive isolation, and as appropriate, purification from a reaction mixture, and formulation into an efficacious therapeutic agent.

As used herein, these abbreviations have the following meanings, respectively: "MIC" is minimum inhibitory concentration.

"MBC is minimum bactericidal concentration.

"MABA" is mycobacterial alamar blue assay.

"MTB" is Mycobacterium tuberculosis.

"DMSO" is dimethylsulfoxide.

"GKO" is gamma-interferon knockout.

"CLSI" is Clinical and Laboratory Standards Institute.

"LORA" is low oxygen recovery assay.

"PA-824" is (65)-2-nitro-6-{ [4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,l- &][l,3]oxazine:

TMC207 is (l«,25')-l-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(l-naphthyl)-l- phenyl-butan-2-ol:

In the specification, the singular forms also include the plural, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present specification will control.

All percentages and ratios used herein, unless otherwise indicated, are by weight.

Throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously. 2. Methods, Compositions and Uses of the Invention

The present invention relates to a method of treating a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising administering a pharmaceutically effective amount of an antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer to a patient.

The present invention relates to a method of preventing a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising administering a prophylactically effective amount of an antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer to a patient.

The present invention relates to a method of reducing the risk of a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising administering a

prophylactically effective amount of an antibiotic compound or tautomer thereof or

pharmaceutically acceptable salt or prodrug of said compound or tautomer to a patient.

In one aspect, the present invention relates to a method, wherein the infection is caused or mediated by Mycobacterium tuberculosis. In one aspect, the infection is caused or mediated by a nontuberculous mycobacterium.

The present invention relates to a composition for treating a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising a pharmaceutically effective amount of an antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer. The present invention relates to a composition for preventing a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising a prophylactically effective amount of an antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer.

The present invention relates to a composition for reducing the risk of a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising a prophylactically effective amount of an antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer.

In one aspect, the present invention relates to a composition, where in the infection is caused or mediated by Mycobacterium tuberculosis. In one aspect, the infection is caused or mediated by a nontuberculous mycobacterium.

The present invention relates to a use of an antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer in the manufacture of a medicament for treating a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising administering a pharmaceutically effective amount of an antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer to a patient.

The present invention relates to a use of an antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer in the manufacture of a medicament for preventing a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising administering a prophylactically effective amount of an antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer to a patient. The present invention relates to a use of an antibiotic compound in the manufacture of a medicament for reducing the risk of a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising administering a prophylactically effective amount of an antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer to a patient.

In one aspect, the present invention relates to a use, wherein the infection is caused or mediated by Mycobacterium tuberculosis. In another aspect, the infection is caused or mediated by a nontuberculous mycobacterium.

In one aspect, the present invention relates to a method, composition, or use, wherein the patient is a mammal or a domestic animal. In one aspect, the patient is a human.

In one aspect, the present invention relates to a method, composition, or use, wherein the antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer is administered orally. In one aspect, the antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer is administered via inhalation. In one aspect, the antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer is administered topically. In one aspect, the antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer is administered parenterally. In one aspect, the antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer is administered intravenously.

In one aspect, the present invention relates to a method, composition, or use, wherein the antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer is selected from an oxazolidinone antibiotic compound.

In one aspect, the antibiotic compound is

or a tautomer thereof or a pharmaceutically acceptable salt or prodrug said compound or tautomer.

In one aspect, the present invention relates to the method, composition, or use, wherein said antibiotic compound is a non-toxic inorganic or organic acid salt. In one aspect, the present invention relates to the method, composition, or use, wherein the non-toxic inorganic or organic acid salt is selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sutfanilic, sulfuric, tannic, tartaric, and toluene sulfonic. In one aspect, the present invention relates to the method, composition, or use, wherein the acid is hydrochloric.

In one aspect, the present invention relates to a method, composition or use, further comprising an additional pharmaceutical compound or salt thereof, particularly, one or more compounds typically used for treating, preventing, or reducing the risk of an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular those infections caused or mediated by resistant or highly virulent strain of a mycobacterium. In one aspect, the present invention relates to a method, composition, or use, wherein the infection is caused or mediated by Mycobacterium tuberculosis. In another aspect, the infection is caused or mediated by a nontuberculous mycobacterium.

In one aspect, the present invention relates to a method, composition or use, further comprising one or more compounds selected from the group consisting of isoniazid, rifampin, rifapentine, rifabutin, ethambutol, pyrazinamide, cycloserine, ethionamide, levofloxacin, moxifloxacin, delafloxacin, nitroimidazoles like PA-824, mycobacterial gyrase inhibitors outside the quinolone class, riminophenazines, InhA inhibitors distinct from isoniazid, new generation diarylquinolines like TMC207, LeuRS inhibitors, tryptanthrins, inhibitors of mycobacterial glyoxylate pathway, non-rifamycin inhibitors of RNA polymerase, menaquinone biosynthesis inhibitors, topoisomerase I inhibitors, mycobacteterial protease inhibitors, gatifloxacin, p- aminosalicylic acid, streptomycin, amikacin, kanamycin, and capreomycin.

In one aspect, the present invention relates to a method, composition or use, wherein the infection is caused or mediated by Mycobacterium tuberculosis and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, wherein the antibiotic compound is:

, or a tautomer thereof or a

pharmaceutically acceptable salt or prodrug of said compound or tautomer, wherein γ-interferon is not administered to said patient and the method, composition, or use is effective against strains recovering from latency.

In one aspect, the present invention relates to a method, composition, or use comprising administering to a patient in need thereof a safe and effective amount of an antibiotic compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer.

As discussed above, infections caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacterial microorganisms pose a risk for patients. Examples of nontuberculous (i.e. nontuberculosis) mycobacteria include, inter alia, Mycobacterium avium (also MAC which is referred to as mycobacterial avium complex which is a combination of strains), Mycobacterium intracellular, MAC, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium fortuitum, Mycobacterium terrae, Mycobacterium xenopi,

Mycobacterium simiae, Mycobacterium marinum, Mycobacterium szulgai, and Mycobacterium malmoense.

It is found that the antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers of the present invention are useful for treating, preventing, or reducing the risk of these microbial infections. The methods of the present invention can be usefully applied to patients, whether human or animal. More particularly it is found that the antibiotic agents useful herein generally are effective against the mycobacterial microorganisms of interest at relatively low concentrations, i.e. the compounds are relatively potent. Consequently, these compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers of the present invention have the potential advantage during administration of less undesired side effects and toxicities and undesired drug-drug interactions. This potential advantage can in turn mean that the compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers of the present invention can be administered for relatively long durations and in combination with other agents. Therefore, the methods, compositions, and uses of the present invention have the potential for better safety, efficacy, and patient compliance relative to currently available therapies.

In practicing the methods of the present invention, it is desired that the tissue and or blood level in the patient or subject, of the compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer used to provide the effect be of an appropriate level for a sufficient time interval. Also, because it often takes a finite amount of time to achieve such blood or tissue levels, it is important that the compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer is administered at some appropriate time. The appropriate time for administration of the compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer will depend upon the pharmacokinetic profile of the compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer and its formulation, route of administration, time required for completing administration, patient characteristics, desired clinical outcome, etc.

3. Antibiotic Compounds Useful in the Present Invention

The antibiotic, i.e. antimicrobial compounds or antibiotic agents useful herein are those that are particularly effective against infections caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.

A wide range of antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers can be used in the methods, compositions, and uses of the present invention. These antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomer scan provide their therapeutic effect by a variety of biochemical or biophysical mechanisms.

Antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers useful in the present invention can include those which bind to or modulate ribosomal RNA, for example bacterial ribosomal RNA. Antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers also useful in the present invention can include those which bind to or modulate the large ribosomal subunit, for example the large ribosomal subunit of a bacterial organism.

Nonlimiting classes of antibiotic compounds useful herein include oxazolidinone antibiotics. Oxazolidinone antibiotics are characterized in having an oxazolidinone ring. The antibiotic compounds useful in the present invention can include their

pharmaceutically acceptable salts, esters, tautomers, or prodrugs thereof. The invention further provides methods for synthesizing any one of the antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers of the present invention. The invention also provides pharmaceutical compositions comprising an effective amount of one or more of the antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers of the present invention and a pharmaceutically acceptable carrier. The present invention further provides methods for making these pharmaceutical compositions. a. Oxazolidinone Antimicrobial Compounds

Oxazolidinone antimicrobial compounds or tautomers thereof and their pharmaceutically acceptable salts, esters, and prodrugs thereof, can be used in the methods, compositions, and uses of the present invention.

Oxazolidinone antimicrobial compounds are described in U.S. Patent No. 7,456,206 B2, to Lou et al., issued November 25, 2008; U.S. Patent No. 7,148,219 B2, to Lou et al., issued December 12, 2006, and its certification of correction of March 4, 2008; U.S. Patent No.

7,129,259 B2, to Chen et al., issued October 31, 2006, and its certificate of correction of March 6, 2007; U.S. Patent No. 6,969,726 B2, to Lou et al., issued November 29, 2005, and its certificates of correction of February 27, 2007 and November 27, 2007; and U.S. Patent No. 5,688,792, to Barbachyn et al., issued November 18, 1997.

Nonlimiting examples of oxazolidione antimicrobial agents useful herein include the following compound:

or a tautomer thereof, or a pharmaceutically acceptable salt or prodrug of said compound or tautomer. Examples of salts include the hydrochloride salt. A further example of a salt is the monohydrochloride salt. The foregoing compound corresponds to the chemical name, inter alia, N-[3-(2-Fluoro-4'-{ [(3H-[l,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo- oxazolidin-5-(S)-ylmethyl]-acetamide. This compound is also known by the USAN, radezolid, and corresponds to the CAS registry number 869884-78-6. The monohydrochloride salt is known by the USAN, radezolid hydrochloride, and to the CAS registry number 869884-77-5.

Other oxazolidinone antimicrobial compounds useful herein include linezolid and torezolid.

Yet other nonlimiting examples of antibiotic compounds useful herein and their pharmaceutically salts, esters, tautomers, and prodrugs thereof are disclosed in the documents cited in Table 1. These documents and their disclosures are incorporated by reference herein in their entirety.

Table 1

References Disclosing Antibiotic Compounds of the Present Invention

PCT Applicant or Title Publication International

Publication Assignee or Issue Date or U.S. Filing No., U.S. Date

Patent No., or

U.S.

Application

Serial No.

WO Rib-X Treatment of November May 15, 2007

Pharmaceutic als , Mycobacterial Infections 22, 2007

2007/133803

Inc. WO Rib-X Process for the Synthesis December 14, June 8, 2006

Pharmaceutic als , of Triazoles

2006/133397 2006

Inc.

WO Rib-X Biaryl Heterocyclic March 2, December 1,

2006/022794 Pharmaceutic als , Compounds and Methods 2006 2004

Inc. of Making and Using the

Same

WO Rib-X Halogenated Biaryl July 7, 2005 December 1,

2005/061468 Pharmaceutic als , Heterocyclic Compounds 2004

Inc. and Methods of Making

and Using The Same

WO Rib-X Sulfonamide Compounds August 4, June 2, 2004

2005/070904 Pharmaceutic als , and Methods of Making 2005

Inc. and Using The Same

WO Rib-X Biaryl Heterocyclic March 3, Junse 2, 2004

Pharmaceutic als , Compounds and Methods

2005/019211 2005

Inc. of Making and Using the

Same

WO Rib-X Biaryl Heterocyclic February 10, July 28, 2004

2005/012270 Pharmaceutic als , Amides, Amides, and 2005

Inc. Sulfur- Containing

Compounds and Methods

of Making and Using the

Same

WO Rib-X Process for the Synthesis February 10, July 28, 2004

2005/012271 Pharmaceutic als , of Biaryl Oxazolidinones 2005

Inc.

WO Dong-A Pharm. Novel Oxazolidione June 30, 2005 December 17,

Co., Ltd. Derivatives 2004

2005/058886

US 6,559,303 Pharmacia & Linezolide-Crystal Form May 6, 2003 May 23, 2002 Bl Upjohn II

Company

US 5,688,792 Pharmacia & Substituted Oxazine and November § 371 Date

Upjohn Thiazine Oxazolidinone 18, 1997 March 5, 1996

Company Antimicrobials

US 5,654,435 Pharmacia & Substituted August 5, June 6, 1995

Upjohn Arylphenyloxazolidinones 1997

Company

WO Dong A Pharm. Novel Oxazolidinone December 13, May 18, 2001

2001/094342 Co., Ltd. Derivatives and a Process 2001

for the Preparation

Thereof

WO AstraZeneca AB Oxazolidinone November 1, April 23, 2001

01/081350 and AstraZeneca Derivatives with 2001 UK Limited Antibiotic Activity

U.S. Patent Rib-X Biaryl Heterocyclic November June 2, 2004 No. 6,969,726 Pharmaceutic als , Compounds and Methods 29, 2005

B2 and its Inc. of Making and Using the

certificates of Same

correction of

February 27,

2007 and

November 27,

2007

U.S. Patent Rib-X Biaryl Heterocyclic December 12, April 29, 2005 No. 7,148,219 Pharmaceutic als , Compounds and Methods 2006

B2 and its Inc. of Making and Using the

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correction of

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U.S. Patent Rib-X Biaryl Heterocyclic November July 14, 2006 No. 7,456,206 Pharmaceutic als , Compounds and Methods 25, 2008

B2 and its Inc. of Making and Using the

certificate of Same

correction of

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2009

U.S. Patent Rib-X Biaryl Heterocyclic April 27, November 21, No. 7,705,026 Pharmaceutic als , Compounds and Methods 2010 2008

B2, ands its Inc. of Making and Using the

certficate of Same

correction of

March 5, 2011

The dose of the oxazolidinone antimicrobial agent and mode of administration of the pharmaceutical composition will depend upon the intended patient or subject and the targeted microorganism, e.g., the target bacterial organism.

or a pharmaceutically acceptable salt or prodrug thereof. Examples of salts include the hydrochloride salt. A further example of a salt is the monohydrochloride salt. The foregoing compound corresponds to the chemical name, inter alia, N-[3-(2-Fluoro-4'-{ [(3H-[l,2,3]triazol-4- ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide. This compound is also known by the USAN, radezolid, and corresponds to the CAS registry number 869884-78-6. The monohydrochloride salt is known by the USAN, radezolid hydrochloride, and to the CAS registry number 869884-77-5.

The oxazolidinone antimicrobial agent is used in a weight percentage in the composition to provide the desired pharmacological properties, such as e.g. drug bioavailability from the final composition. Weight percentages of the oxazolidinone antimicrobial agent range from about 0.01% to about 5%. In further embodiments, weight percentages range from about 0.1% to about 0.5%. In further embodiments, weight percentages range from about 0.25% to about 0.40%.

Other Aspects of the Compounds of the Present Invention

Antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers designed, selected and/or optimized for use in the present invention, after being produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds or tautomers thereof or

pharmaceutically acceptable salts or prodrugs of said compounds or tautomers have biological activity. For example, the antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers can be characterized by

conventional assays, including but not limited to those assays described below, to determine whether the compounds have a predicted activity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to screen rapidly the molecules described herein for activity, for example as anti-bacterial. Also, it can be possible to assay how the compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers interact with a ribosome or ribosomal subunit and/or are effective as modulators (for example, inhibitors) of protein synthesis using techniques known in the art. General

methodologies for performing high-throughput screening are described, for example, in Devlin, High Throughput Screening, (Marcel Dekker, 1998); and U.S. Patent No. 5,763,263. High- throughput assays can use one or more different assay techniques including, but not limited to, those described below.

(1) Surface Binding Studies. A variety of binding assays can be useful in screening new molecules for their binding activity. One approach includes surface plasmon resonance (SPR) that can be used to evaluate the binding properties of molecules of interest with respect to a ribosome, ribosomal subunit or a fragment thereof.

SPR methodologies measure the interaction between two or more macromolecules in real-time through the generation of a quantum-mechanical surface plasmon. One device, (BIAcore Biosensor RTM from Pharmacia Biosensor, Piscataway, N.J.) provides a focused beam of polychromatic light to the interface between a gold film (provided as a disposable biosensor "chip") and a buffer compartment that can be regulated by the user. A 100 nm thick "hydrogel" composed of carboxylated dextran that provides a matrix for the covalent immobilization of analytes of interest is attached to the gold film. When the focused light interacts with the free electron cloud of the gold film, plasmon resonance is enhanced. The resulting reflected light is spectrally depleted in wavelengths that optimally evolved the resonance. By separating the reflected polychromatic light into its component wavelengths (by means of a prism), and determining the frequencies that are depleted, the BIAcore establishes an optical interface which accurately reports the behavior of the generated surface plasmon resonance. When designed as above, the plasmon resonance (and thus the depletion spectrum) is sensitive to mass in the evanescent field (which corresponds roughly to the thickness of the hydrogel). If one component of an interacting pair is immobilized to the hydrogel, and the interacting partner is provided through the buffer compartment, the interaction between the two components can be measured in real time based on the accumulation of mass in the evanescent field and its corresponding effects of the plasmon resonance as measured by the depletion spectrum. This system permits rapid and sensitive real-time measurement of the molecular interactions without the need to label either component.

(2) Fluorescence Polarization. Fluorescence polarization (FP) is a measurement technique that can readily be applied to protein-protein, protein-ligand, or RNA-ligand interactions in order to derive IC5₀S and Kds of the association reaction between two molecules. In this technique one of the molecules of interest is conjugated with a fluorophore. This is generally the smaller molecule in the system (in this case, the compound of interest). The sample mixture, containing both the ligand-probe conjugate and the ribosome, ribosomal subunit or fragment thereof, is excited with vertically polarized light. Light is absorbed by the probe fluorophores, and re-emitted a short time later. The degree of polarization of the emitted light is measured. Polarization of the emitted light is dependent on several factors, but most importantly on viscosity of the solution and on the apparent molecular weight of the fluorophore. With proper controls, changes in the degree of polarization of the emitted light depends only on changes in the apparent molecular weight of the fluorophore, which in-turn depends on whether the probe-ligand conjugate is free in solution, or is bound to a receptor. Binding assays based on FP have a number of important advantages, including the measurement of IC5₀S and Kds under true homogenous equilibrium conditions, speed of analysis and amenity to automation, and ability to screen in cloudy suspensions and colored solutions.

(3) Protein Synthesis. It is contemplated that, in addition to characterization by the foregoing biochemical assays, the compound of interest can also be characterized as a modulator (for example, an inhibitor of protein synthesis) of the functional activity of the ribosome or ribosomal subunit.

Furthermore, more specific protein synthesis inhibition assays can be performed by administering the compound to a whole organism, tissue, organ, organelle, cell, a cellular or subcellular extract, or a purified ribosome preparation and observing its pharmacological and inhibitory properties by determining, for example, its inhibition constant (IC₅₀) for inhibiting protein synthesis. Incorporation of ³H leucine or ³⁵S methionine, or similar experiments can be performed to investigate protein synthesis activity. A change in the amount or the rate of protein synthesis in the cell in the presence of a molecule of interest indicates that the molecule is a modulator of protein synthesis. A decrease in the rate or the amount of protein synthesis indicates that the molecule is a inhibitor of protein synthesis.

Furthermore, the antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers can be assayed for anti-proliferative or anti-infective properties on a cellular level. For example, where the target organism is a microorganism, the activity of compounds of interest can be assayed by growing the

microorganisms of interest in media either containing or lacking the compound. Growth inhibition can be indicative that the molecule could be acting as a protein synthesis inhibitor. More specifically, the activity of the compounds of interest against bacterial pathogens can be demonstrated by the ability of the compound to inhibit growth of defined strains of human pathogens, particularly P. acnes and P. granulosum and resistant strains thereof. For this purpose, a panel of bacterial strains can be assembled to include a variety of target pathogenic species, some containing resistance mechanisms that have been characterized. Use of such a panel of organisms permits the determination of structure- activity relationships not only in regards to potency and spectrum, but also with a view to obviating resistance mechanisms. The assays can be performed in microtiter trays according to conventional methodologies as published by The National Committee for Clinical Laboratory Standards (NCCLS) guidelines (NCCLS. M7-A5-Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Fifth Edition. NCCLS Document M100-S12/M7 (ISBN 1-56238-394-9)).

4. Formulation and Administration

The methods of the present invention can be practiced by delivering the antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers of the present invention using any suitable carrier. The dose of antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer, mode of administration and use of suitable carrier will depend upon the intended patient or subject and the targeted microorganism, e.g., the target bacterial organism.

The formulations, both for human medical use and veterinary use, of the antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers according to the present invention typically include such antibiotic compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers in association with a pharmaceutically acceptable carrier.

The carrier(s) should be "acceptable" in the sense of being compatible with compounds or tautomers thereof or pharmaceutically acceptable salts or prodrugs of said compounds or tautomers of the present invention and not deleterious to the recipient. Pharmaceutically acceptable carriers, in this regard, are intended to include any and all solvents, dispersion media, coatings, absorption delaying agents, and the like, compatible with pharmaceutical

administration. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer, use thereof in the compositions is contemplated. Supplementary active compounds (identified or designed according to the invention and/or known in the art) or tautomers thereof or a pharmaceutically acceptable salts or prodrugs of said compounds or tautomers also can be incorporated into the compositions. The formulations can conveniently be presented in dosage unit form and can be prepared by any of the methods well known in the art of pharmacy/microbiology. In general, some formulations are prepared by bringing the compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

A pharmaceutical composition of the invention can be formulated to be compatible with its intended route of administration. These can include solids and semisolids. Solutions or suspensions can include the following components: a sterile diluent such as water, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

A wide variety of formulations and administration methods can be found in S.K. Niazi, ed., Handbook of Pharmaceutical Formulations, Vols. 1-6 [Vol. 1 Compressed Solid Products, Vol. 2 Uncompressed Drug Products, Vol. 3 Liquid Products, Vol. 4 Semi-Solid Products, Vol. 5 Over the Counter Products, and Vol. 6 Sterile Products], CRC Press, April 27, 2004.

Useful solutions for oral or parenteral administration can be prepared by any of the methods well known in the pharmaceutical art, described, for example, in Remington 's

Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). Formulations for parenteral administration can also include glycocholate for buccal administration,

methoxysalicylate for rectal administration, or citric acid for vaginal administration. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Suppositories for rectal administration also can be prepared by mixing the drug with a non-irritating excipient such as cocoa butter, other glycerides, or other compositions which are solid at room temperature and liquid at body temperatures.

Formulations also can include, for example, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, and hydrogenated naphthalenes. Formulations for direct administration can include glycerol and other compositions of high viscosity. Other potentially useful parenteral carriers for these drugs include ethylene- vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration can contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Retention enemas also can be used for rectal delivery.

Formulations of the present invention suitable for oral administration can be in the form of: discrete units such as capsules, gelatin capsules, sachets, tablets, troches, or lozenges, each containing a predetermined amount of the drug; a powder or granular composition; a solution or a suspension in an aqueous liquid or non-aqueous liquid; or an oil-in-water emulsion or a water- in-oil emulsion. The drug can also be administered in the form of a bolus, electuary or paste. A tablet can be made by compressing or molding the drug optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the drug in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered drug and suitable carrier moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound or tautomer thereof or a

pharmaceutically acceptable salt or prodrug of said compound or tautomer can be incorporated with excipients. Oral compositions prepared using a fluid carrier for use as a mouthwash include the compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer in the fluid carrier and are applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as

microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Formulations suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the drug that can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic

administration.

Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in- oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment or soap. Useful are carriers capable of forming a film or layer over the skin to localize application and inhibit removal. For topical administration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface. For example, hydroxypropylcellulose or fibrinogen/thrombin solutions can be used to advantage. Alternatively, tissue-coating solutions, such as pectin-containing formulations can be used.

Additionally, the carrier for a topical formulation can be in the form of a hydroalcoholic system (e.g. quids and gels), an anhydrous oil or silicone based system, or an emulsion system, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in- silicone emulsions. The emulsions can cover a broad range of consistencies including thin lotions (which can also be suitable for spray or aerosol delivery), creamy lotions, light creams, heavy creams, and the like. The emulsions can also include microemulsion systems. Other suitable topical carriers include anhydrous solids and semisolids (such as gels and sticks); and aqueous based mousse systems. Nonlimiting examples of the topical carrier systems useful in the present invention are described in the following four references, all of which are incorporated herein by reference in their entirety: "Sun Products Formulary", Cosmetics & Toiletries, vol. 105, pp. 122-139 (December 1990); "Sun Products Formulary", Cosmetics & Toiletries, vol. 102, pp. 117-136 (March 1987); U.S. Pat. No. 4,960,764 to Figueroa et al., issued Oct. 2, 1990; and U.S. Pat. No. 4,254,105 to Fukuda et al., issued Mar. 3, 1981.

The pharmaceutically-acceptable topical carriers, in total, typically comprise from about 0.1% to about 99.8% by weight of the compositions useful in the present invention, preferably from about 80% to about 99%, and most preferably from about 85% to about 95%.

For inhalation treatments, inhalation of powder (self-propelling or spray formulations) dispensed with a spray can, a nebulizer, or an atomizer can be used. Such formulations can be in the form of a fine powder for pulmonary administration from a powder inhalation device or self- propelling powder-dispensing formulations. In the case of self-propelling solution and spray formulations, the effect can be achieved either by choice of a valve having the desired spray characteristics (i.e., being capable of producing a spray having the desired particle size) or by incorporating the active ingredient as a suspended powder in controlled particle size. For administration by inhalation, the compounds or tautomers thereof or a pharmaceutically acceptable salts or prodrugs of said compounds or tautomers also can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration also can be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants generally are known in the art, and include, for example, for transmucosal administration, detergents and bile salts. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds or tautomers thereof or a pharmaceutically acceptable salts or prodrugs of said compounds or tautomers typically are formulated into ointments, salves, gels, or creams as generally known in the art.

The active compounds or tautomers thereof or a pharmaceutically acceptable salts or prodrugs of said compounds or tautomers can be prepared with carriers that will protect the compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, poly anhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

Oral or parenteral compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer and the therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer for the treatment of individuals.

Furthermore, administration can be by periodic injections of a bolus, or can be made more continuous by intravenous, intramuscular or intraperitoneal administration from an external reservoir (e.g., an intravenous bag).

Where adhesion to a tissue surface is desired the composition can include the drug dispersed in a fibrinogen-thrombin composition or other bioadhesive. The compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer then can be painted, sprayed or otherwise applied to the desired tissue surface. Alternatively, the drugs can be formulated for parenteral or oral administration to humans or other mammals, for example, in effective amounts, e.g., amounts that provide appropriate concentrations of the drug to target tissue for a time sufficient to induce the desired effect.

In conjunction with the methods of the present invention, pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) can be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a drug as well as tailoring the dosage and/or therapeutic regimen of treatment with the drug.

Generally, an effective amount of dosage of active compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer will be in the range of from about 0.01 to about 100 mg/kg of body weight/day. The amount administered will also likely depend on such variables as the condition to be treated, the severity of the condition, the age and overall health status of the patient, the relative biological efficacy of the compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer delivered, the formulation of the compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer, the presence and types of excipients in the formulation, and the route of administration. Also, it is to be understood that the initial dosage administered can be increased beyond the above upper level in order to rapidly achieve the desired tissue level or blood level, or the initial dosage can be smaller than the optimum.

Nonlimiting doses of active compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer comprise from about 0.1 to about 1500 mg per dose. Nonlimiting examples of doses, which can be formulated as a unit dose for convenient administration to a patient include: about 0.1 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15, mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050, mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, and about 1500 mg. The foregoing doses are useful for administering the compounds or tautomers thereof or pharmaceutically acceptable salts or prodrug of said compounds or tautomers of the present invention according to the methods of the present invention.

Other Embodiments

In other embodiments, the present invention relates to a method composition or use further comprising an additional pharmaceutical agent, particularly, one or more compounds typically used for treating, preventing, or reducing the risk of an infection caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria.

In February 2003, the American Thoracic Society (ATS), the Centers for Diseases Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA) released new guidelines for the treatment of tuberculosis. See, Centers for Disease Control and

Prevention, Treatment of Tuberculosis, Morbidity and Mortality Weekly Report, Vol 52, No. RR-11, June 20, 2003 and the associated errata January 7, 2005 / 53(51 & 52); 1203.

Nonlimiting examples of such compounds include, e.g., isoniazid, rifampin, rifapentine, rifabutin, ethambutol, pyrazinamide, cycloserine, ethionamide, levofloxacin, moxifloxacin, delafloxacin, nitroimidazoles like PA-824, mycobacterial gyrase inhibitors outside the quinolone class, riminophenazines, InhA inhibitors distinct from isoniazid, new generation diarylquinolines like TMC207, LeuRS inhibitors, tryptanthrins, inhibitors of mycobacterial glyoxylate pathway, non-rifamycin inhibitors of RNA polymerase, menaquinone biosynthesis inhibitors,

topoisomerase I inhibitors, mycobacteterial protease inhibitors, gatifloxacin, ^-aminosalicylic acid, streptomycin, amikacin, kanamycin, and capreomycin.

Optional Components

In addition to the required components of the compositions useful in the present invention, a variety of optional components can also be incorporated. Vitamin B6 - Vitamin B6 can be used in combination with the compounds used in the present invention, as it is used for alleviating the associated numbness and tingling in the hands and feet.

NSAIDS - Also useful, particularly for oral and topical compositions are non-steroidal anti- inflammatory drugs (NSAIDS). The NSAIDS can be selected from the following categories: propionic acid derivatives; acetic acid derivatives; fenamic acid derivatives; biphenylcarboxylic acid derivatives; and oxicams. All of these NSAIDS are fully described in the U.S. Pat. No. 4,985,459 to Sunshine et al., issued Jan. 15, 1991, incorporated by reference herein. Most preferred are the propionic NSAIDS including but not limited to aspirin, acetaminophen, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen and bucloxic acid. Also useful are the steroidal anti-inflammatory drugs including hydrocortisone and the like. Surfactants The compositions useful in the methods of the present invention, particularly the topical compositions, can optionally comprise one or more surfactants. The surfactants can be present at a level from about 0.1% to about 10%, alternatively from about 0.2% to about 5%, and yet alternatively from about 0.2% to about 2.5%. Suitable surfactants include, but are not limited to, nonionic surfactants such as polyalkylene glycol ethers of fatty alcohols, and anionic surfactants such as taurates and alkyl sulfates. Nonlimiting examples of these surfactants include isoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, and sodium lauryl sulfate. See U.S. Pat. No. 4,800,197, to Kowcz et al., issued Jan. 24, 1989, which is incorporated herein by reference in its entirety. Examples of a broad variety of additional surfactants useful herein are described in McCutcheon's, Detergents and Emulsifiers, North American Edition (1986), published by Allured Publishing Corporation, which is incorporated herein by reference in its entirety.

EXAMPLES

The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention. Ingredients are identified by chemical or CTFA name.

EXAMPLE 1

Tablet for Oral Administration

Ingredients Per Tablet Per 4000 Tablets

OxazolidinoneAntibiotic Compound

0.1 - 1500 mg 0.4 - 6000 g

Anhydrous Lactose, NF 110.45 mg 441.8 g

Microcrystalline 80.0 mg 320.0 g

Cellulose NF

Magnesium Stearate 1.00 mg 4.0 g

Impalpable Powder NF

Croscarmellose Sodium 2.00 mg 8.0 g

NF Type A

The oxazolidinone antibiotic compound or tautomer thereof or a pharmaceutically acceptable salt or prodrug of said compound or tautomer, equivalent to the desired delivery strength, e.g., 0.1 to 1500 mg per tablet) is premixed with 1/3 of the microcrystalline cellulose NF and 1/2 of the anhydrous lactose NF in a ribbon blender for 5 minutes at 20 RPM. To the premix is added the remaining 2/3 of the microcrystalline cellulose NF and the remaining 1/2 of the anhydrous lactose NF. This is blended for 10 minutes at 20 RPM. Crosscarmellose sodium is added to the blended powders and mixed for 5 minutes at 20 RPM. Finally the magnesium stearate is added to the mixture by passing through a 90 mesh screen and blended for an additional 5 minutes at 20 RPM. The lubricated mixture is compressed to provide tablets containing 0.1-1500 mg active ingredient per tablet.

These tablets are useful for administration to a patient for treating, preventing, or reducing the risk of infections caused or mediated by Mycobacterium tuberculosis or nontuberculous mycobacteria and in particular those infections caused or mediated by resistant or highly virulent strains of mycobacteria. EXAMPLE 2

Anti-tuberculosis Activity of Radezolid

Radezolid is a protein synthesis inhibitor that enters bacteria and binds to the 50S ribosomal subunit. Radezolid accumulates in the cytoplasm and lysosomes (not the

mitochondria) of macrophages and demonstrates bactericidal activity toward intracellular pathogens such as S. aureus and L. pneumophila. M. tuberculosis (MTB) is also an intracellular pathogen found in the lysosomes and cytoplasm of immune cells. Given these properties, radezolid was tested for activity against MTB grown aerobically and in a low-oxygen recovery assay (LORA- a surrogate test for potency versus latent organisms). Given the favorable preclinical and clinical profiles of radezolid, especially its ability to concentrate in the lysosomes of infected macrophages, radezolid was tested for activity against M. tuberculosis.

Methods: In vitro activity of drugs against MTB was determined with the mycobacterial alamar blue assay (MABA), and reported as the amount of drug necessary to reduce bacterial metabolism by 90% (IC90). Activity against MTB recovering from exposure to low oxygen conditions was also measured by alamar blue. Susceptibility data were also collected by determining minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) according to standard CLSI (Clinical and Laboratory Standards Institute) methods.

Antimicrobial activity was measured by MABA as reported (ref. 8). Briefly, MABA is a colorimetric assay using the color change of resazurin (from blue to pink) as an indicator of microbial growth. Mycobacterium tuberculosis H37Rv (H37Rv) was grown in Middlebrook 7H9 broth medium supplemented with 0.2% (v/v) glycerol, 10% ADC (albumin, dextrose, catalase) and 0.05% Tween80. The bacteria were inoculated in lOOmL of 7H9 medium in 1L roller bottles and incubated, with turning, at 37°C in ambient air. When cells reached an OD600 of 0.15 (equivalent to ~ 1.5 xl07 cfu/mL, they were diluted 200-fold in 7H9 medium into the final 96-well assay plate. Compounds were dissolved in 100% DMSO at the appropriate concentration and serially diluted 2-fold in 96-well plates. A volume of 160X compound or 100% DMSO (negative and growth controls) was transferred to plates for a 10-fold dilution in sterile water. 6.25 xL of the 10-fold compound dilution plate were added to 93.75 μΐ of cell suspension for a final concentration of 1% DMSO/7H9 and a final inoculum of -105 cfu/mL. Following incubation for 6 days at 37°C in ambient air, 5 \L of a sterile 0.05% resazurin solution was added to each well. Following two days additional incubation, a visual evaluation and a fluorometric readout were performed. Results were expressed in μg/mL (visual) and as IC90 (the lowest amount of drug necessary to reduce bacterial metabolism by 90%).

LORA was carried out in similar fashion according to published methods (ref. 9) using a luminescent strain of MTB grown under low oxygen conditions and frozen away at -80°C.

ΙΟΟμί of thawed cultures diluted to ~1 x 10E6 cfu/mL were added to 100 μL· of 2-fold serially diluted compounds. Following seven days' incubation at 37°C in 5% C0₂, 100 μΐ of culture was transferred to white 96-well microplates for determination of luminescence following addition of an n-decanyl aldehyde/ethanol solution. Luminescence was measured in a Victor2 134 multilabel reader (PerkinElmer Life Sciences) using a reading time of 1 second. Results were reported as IC90, the lowest drug concentration effecting an inhibition of 90% relative to drug- free controls.

Results: Radezolid was active in vitro, with an IC90 in the MABA of 0.03 ug/ml and 0.31 ug/ml in the LORA. For comparison, the MABA IC90 for isoniazid was 0.03 ug/ml. Isoniazid was not active in the LORA. Radezolid demonstrated an MIC value of 0.312 μg/ml against the drug- sensitive H37Rv strain and showed MICs ranging from <0.078-0.312 μg/ml against clinical isolates of M. tuberculosis singlely resistant to the following antibiotics: streptomycin, isoniazid, kanamycin, ethionamide, ethambutol. The MBC of radezolid against H37Rv was determined to be equal to the MIC (0.312 μg/ml). In mice, radezolid reduced the bacterial load resulting from aerosol challenge with MTB by 1.96 loglO in the lungs and 2.58 loglO in the spleen. The change in log cfu for isoniazid was -2.53 and -2.42 in the lungs and spleen, respectively.

Figure 1. Chemical structures:

Compound A

Linezolid:

able 1. Radezolid is highly potent against M. tuberculosis H37Rv.

Radezolid showed significant activity against the susceptible M. tuberculosis strain H37Rv. In the MABA, radezolid was more potent than comparator oxazolidinones, quinolones, and macrolides. Radezolid and another biaryloxazolidinone from the program (Compound A) had IC90 values similar to those collected for isoniazid. As shown in data from the LORA, when non-replicating cells were exposed to compound, drugs like isoniazid, ethambutol, and linezolid were not effective at inhibiting cell growth and recovery in aerobic conditions. Radezolid was the most active compound tested under these conditions, surpassing the activity of rifampicin and moxifloxacin. Data for radezolid represented the geometric mean value of three replicate experiments. Data for other compounds were the mean values from two test occasions, and rifampicin, ethambutol, and linezolid values were collected from the literature (refs. 8 and 9) or through personal communication with S. Franzlbau. Data with an asterisk were collected from experiments using 7H12 broth. Radezolid is highly active against MTB in vitro and in vivo. Radezolid is highly active in vitro against clinical and laboratory isolates of M. tuberculosis, using the inhibition of bacterial metabolism as a measure of antimycobacterial potency. In fact, radezolid activity is equal or superior to drugs that comprise the first line of therapy for tuberculosis patients (e.g. isoniazid, ethambutol, etc).

Radezolid is perhaps the most active compound tested in these studies for potency against organisms grown under hypoxic conditions. The non-replicating/persistent state of bacteria grown under these in vitro conditions suggests that radezolid may have usefulness in treating latent infections.

EXAMPLE 3

Radezolid in the GKO Mouse Model

The efficacy of radezolid was measured in a gamma-interferon knockout (GKO) mouse model (ref. 10).

Methods: The GKO mouse model was performed according to published methods and drugs were dosed orally: Radezolid at 50 mg/kg BID; isoniazid at 25 mg/kg QD. In vivo efficacy was measured using gamma interferon gene-disrupted mice as reported (ref. 10). Interferon gamma knockout mice (unable to control an infection of MTB) from a C57BL/6 background were infected in the standard manner (aerosol infection with the Erdman strain, utilizing the Glas-Col Inhalation Exposure System). Three mice were sacrificed Day 1 post-infection to determine bacterial uptake. Day 13 post-infection, 5 mice were sacrificed to determine bacterial load in the lungs and spleens. Therapy, administered via oral gavage began Day 13 post-infection and continued for 9 days. Day 22 post-infection the mice are sacrificed and bacterial loads are determined. An isoniazid control group, administered via oral gavage at 25 mg/kg/day was included in each study. Oxazolidinones were dosed orally at 50mg/kg BID in 0.5% Tween80, and 0.5% methylcellulose (in water).

Results:

Table 2 demonstrates that after establishing an infection in gamma interferon knock-out mice over the first thirteen days post inoculation, colony forming units of MTB Erdman reached approximately 6.6E7 and 9.7E3 in the lungs and spleen, respectively. After nine days of once daily (QD) dosing, isoniazid colony counts were reduced 2.53 log 10 in lung compared the untreated controls on day 22. Radezolid reduced cfu in the lung by nearly 2 loglO units, approaching 7.2E5 following twice daily (BID) dosing . Radezolid also prevented MTB from spreading to and/or proliferating in the spleens of GKO mice, showing very similar activity to that of isoniazid. Table 2. Radezolid is efficacious in the GKO Mouse Model

See references related to Examples 2 and 3 : 1) Lawrence L. et al..2008; In vitro activities of the Rx-01 oxazolidinones against hospital and community pathogens. Antimicrob Agents Chemother. Vol 52(5): 1653-62.

2) Skripkin E. et al..2008; Rx-01, a new family of oxazolidinones that overcome ribosome- based linezolid resistance.Antimicrob Agents Chemother. Vol 52(10):3550-7.

3) Lemaire S, Tulkens PM, Van Bambeke F. 2010; Cellular pharmacokinetics of the novel biaryloxazolidinone radezolid in phagocytic cells: studies with macrophages and polymorphonuclear neutrophils. Antimicrob Agents Chemother. Vol 54(6):2540-8.

4) Lemaire S. et al..2010; Cellular pharmacodynamics of the novel biaryloxazolidinone radezolid: studies with infected phagocytic and nonphagocytic cells, using Staphylococcus aureus, Staphylococcus epidermidis, Listeria monocytogenes, and Legionella pneumophila. Antimicrob Agents Chemother. Vol 54(6):2549-59.

5) File Jr., T. et al., 2008; A Phase 2 study comparing two doses of radezolid to linezolid in adults with uncomplicated skin and skin structure infections (uSSSI). 48^th ICAAC, Poster L- 1515c.

6) Keeler, E., et al., 2006; Reducing the global burden of tuberculosis: the contribution of improved diagnostics. Nature, 444 Suppl 1: p. 49-57. 7) Fauci AS and the NIAID Tuberculosis Working Group (2008) Multidrug-resistant and extensively drug -resistant tuberculosis: the National Institute of Allergy and Infectious Diseases Research Agenda and Recommendations for priority research. Journal of Infectious Diseases 197: 1493-1498.

8) Collins, L.A. and S.G. Franzblau, 1997; Microplate Alamar Blue Assay versus BACTEC

460 System for High-throughput Screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob Agents Chemother.41(5): 1004-09.

9) Cho, S.H. et al., 2007; Low-oxygen-recovery assay for high-throughput screening of compounds against nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother. Vol 51(4): 1380-5.

10) Lenaerts A.J. et al, 2003; Rapid in vivo screening of experimental drugs for tuberculosis using gamma interferon gene-disrupted mice. Antimicrob Agents Chemother. Vol 47(2):783-5.

INCORPORATION BY REFERENCE The entire disclosure of each of the patent documents, including certificates of correction, patent application documents, scientific articles, governmental reports, websites, and other references referred to herein is incorporated by reference in its entirety for all purposes.

EQUIVALENTS

The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising administering to said patient a pharmaceutically effective amount of the antibiotic compound:

r° or a tautomer thereof, or a pharmaceutically acceptable salt or prodrug of said compound or tautomer.

2. A method of preventing a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising administering to said patient a prophylactically effective amount the antibiotic compound:

3. A method of reducing the risk of a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising administering to said patient a prophylactically effective amount of the antibiotic compound:

4. The method according to any of Claims 1-3, wherein the infection is caused or mediated by Mycobacterium tuberculosis.

5. The method according to any of Claims 1-3, wherein the infection is caused or mediated by a nontuberculous mycobacterium.

6. A composition for treating a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising a pharmaceutically effective amount of the antibiotic compound:

7. A composition for preventing a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising a prophylactically effective amount of the antibiotic compound:

or a tautomer thereof, or a pharmaceutically acceptable salt or prodrug of said compound or tautomer.

8. A composition for reducing the risk of a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising a prophylactically effective amount of the antibiotic compound:

9. The composition according to any of Claims 6-8, wherein the infection is caused or mediated by Mycobacterium tuberculosis.

10. The composition according to any of Claims 6-8, wherein the infection is caused or mediated by a nontuberculous mycobacterium.

11. Use of the antibiotic compound:

or a tautomer thereof, or a pharmaceutically acceptable salt or prodrug of said compound or tautomer in the manufacture of a medicament for treating a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising administering to said patient a pharmaceutically effective amount of the antibiotic compound.

12. Use of the antibiotic compound:

or a tautomer thereof, or a pharmaceutically acceptable salt or prodrug of said compound or tautomer in the manufacture of a medicament for preventing a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising administering to said patient a prophylactically effective amount of said antibiotic compound.

13. Use of the antibiotic compound:

or a tautomer thereof, or a pharmaceutically acceptable salt or prodrug of said compound or tautomer in the manufacture of a medicament for reducing the risk of a mycobacterial infection, for example an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular an infection caused or mediated by a resistant or highly virulent strain of a mycobacterium, in a patient comprising administering to said patient a prophylactically effective amount of said antibiotic compound.

14. The use according to any of Claims 11-13, wherein the infection is caused or mediated by Mycobacterium tuberculosis.

15. The use according to any of Claims 11-13, wherein the infection is caused or mediated by a nontuberculous mycobacterium.

16. A method, composition, or use according to any of Claims 1-15 wherein said patient is a mammal or a domestic animal.

17. A method, composition, or use according to any of Claims 1-16 wherein said patient is a human.

18. A method, composition, or use according to any of Claims 1-17 wherein said antibiotic compound is administered orally.

19. A method, composition, or use according to any of Claims 1-17 wherein said antibiotic compound is administered via inhalation.

20. A method, composition, or use according to any of Claims 1-17 wherein said antibiotic compound is administered topically.

21. A method, composition, or use according to any of Claims 1-17 wherein said antibiotic compound is administered parenterally.

22. The method of Claim 21, wherein the compound is administered intravenously.

23. The method, composition, or use according to any of Claims 1-22, wherein said antibiotic compound is a non-toxic inorganic or organic acid salt.

24. The method, composition, or use according to Claim 23, wherein the non-toxic inorganic or organic acid salt is selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,

polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sutfanilic, sulfuric, tannic, tartaric, and toluene sulfonic.

25. The method, composition, or use according to claim 24, wherein the acid is hydrochloric.

26. The method, composition, or use according to any of Claims 1 -25, further comprising an additional pharmaceutical compound or salt thereof, particularly, one or more compounds typically used for treating, preventing, or reducing the risk of an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular those infections caused or mediated by resistant or highly virulent strain of a mycobacterium.

27. The method, composition, or use according to Claim 25. wherein the infection is caused or mediated by Mycobacterium tuberculosis.

28. The method, composition, or use according to Claim 25, wherein the infection is caused or mediated by a nontuberculous mycobacterium.

29. The method, composition or use according to any of Claims 1 -28 further comprising one or more compounds selected from the group consisting of isoniazid, rifampin, rifapentine, rifabutin, ethambutol, pyrazinamide, cycloserine, ethionamide, levofloxacin, moxifloxacin, delafloxacin, nitroimidazoles like PA-824, mycobacterial gyrase inhibitors outside the quinolone class, riminophenazines, InhA inhibitors distinct from isoniazid, new generation diarylquinolines like TMC207, LeuRS inhibitors, tryptanthrins, inhibitors of mycobacterial glyoxylate pathway, non-rifamycin inhibitors of RNA polymerase, menaquinone biosynthesis inhibitors, topoisomerase I inhibitors, mycobacterial protease inhibitors, gatifloxacin, p-aminosalicylic acid, streptomycin, amikacin, kanamycin, and capreomycin.