title: A novel inhibitor of gyrase B is a potent drug candidate for treatment of tuberculosis and nontuberculosis mycobacterial infections.
abstract: New drugs to treat drug-resistant tuberculosis are urgently needed. Extensively drug-resistant and probably the totally drug-resistant tuberculosis strains are resistant to fluoroquinolones like moxifloxacin, which target gyrase A, and most people infected with these strains die within a year. In this study, we found that a novel aminobenzimidazole, VXc-486, which targets gyrase B, potently inhibits multiple drug-sensitive isolates and drug-resistant isolates of Mycobacterium tuberculosis in vitro (MICs of 0.03 to 0.30 μg/ml and 0.08 to 5.48 μg/ml, respectively) and reduces mycobacterial burdens in lungs of infected mice in vivo. VXc-486 is active against drug-resistant isolates, has bactericidal activity, and kills intracellular and dormant M. tuberculosis bacteria in a low-oxygen environment. Furthermore, we found that VXc-486 inhibits the growth of multiple strains of Mycobacterium abscessus, Mycobacterium avium complex, and Mycobacterium kansasii (MICs of 0.1 to 2.0 μg/ml), as well as that of several strains of Nocardia spp. (MICs of 0.1 to 1.0 μg/ml). We made a direct comparison of the parent compound VXc-486 and a phosphate prodrug of VXc-486 and showed that the prodrug of VXc-486 had more potent killing of M. tuberculosis than did VXc-486 in vivo. In combination with other antimycobacterial drugs, the prodrug of VXc-486 sterilized M. tuberculosis infection when combined with rifapentine-pyrazinamide and bedaquiline-pyrazinamide in a relapse infection study in mice. Furthermore, the prodrug of VXc-486 appeared to perform at least as well as the gyrase A inhibitor moxifloxacin. These findings warrant further development of the prodrug of VXc-486 for the treatment of tuberculosis and nontuberculosis mycobacterial infections.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA Christopher_locher@hotmail.com.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Locher
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jones
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Hanzelka
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Perola
authors.affiliation: Central New York Research Corporation, Syracuse, New York, USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Shoen
authors.affiliation: Central New York Research Corporation, Syracuse, New York, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cynamon
authors.affiliation: DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/MRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Andile H
authors.initials: AH
authors.lastname: Ngwane
authors.affiliation: DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/MRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Wiid
authors.affiliation: DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/MRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Helden
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Betoudji
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Thomson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009164:Mycobacterium Infections / Q000188:drug therapy*; D059005:Topoisomerase II Inhibitors / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D059005:Topoisomerase II Inhibitors; C000603606:VXc-486