title: In vitro and in vivo activities of three oxazolidinones against nonreplicating Mycobacterium tuberculosis.
abstract: Oxazolidinones represent a new class of antituberculosis drugs that exert their function by inhibiting protein synthesis. Here, we compared the activities of three oxazolidinones, linezolid, PNU-100480, and AZD5847, against latent tuberculosis using a simple model employing the streptomycin-starved Mycobacterium tuberculosis strain 18b. The in vitro drug susceptibility results showed that the three oxazolidinones had a bacteriostatic effect against actively growing bacilli but potent bactericidal activity against nonreplicating cells. In the murine model of latent infection with M. tuberculosis 18b, the efficacy of the three compounds varied greatly. Indeed, AZD5847 or its prodrug exhibited no activity or only modest activity, respectively, after 2 months of treatment, whereas both linezolid and PNU-100480 were effective against latent bacilli in mice and showed promising outcomes in combination therapy with rifampin. Moreover, the potency of PNU-100480 was significantly greater than that of linezolid, making it an attractive drug candidate in the development of new combination therapies for latent tuberculosis.
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sala
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhar
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Anthony
authors.initials: A
authors.lastname: Vocat
authors.affiliation: AstraZeneca India Pvt., Ltd., Hebbal, Bangalore, India.
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
authors.affiliation: AstraZeneca India Pvt., Ltd., Hebbal, Bangalore, India.
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Marriner
authors.affiliation: AstraZeneca India Pvt., Ltd., Hebbal, Bangalore, India.
authors.forename: V
authors.initials: V
authors.lastname: Balasubramanian
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland stewart.cole@epfl.ch.
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
mesh_terms: D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D005260:Female; D000860:Hypoxia; D055985:Latent Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D000069349:Linezolid; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D023303:Oxazolidinones / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000081:Acetamides; D000995:Antitubercular Agents; D023303:Oxazolidinones; C543015:PNU-100480; C453362:posizolid; D000069349:Linezolid