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  2. A novel inhibitor of gyrase B is a potent drug candidate for treatment of tuberculosis and nontuberculosis mycobacterial infections

A novel inhibitor of gyrase B is a potent drug candidate for treatment of tuberculosis and nontuberculosis mycobacterial infections

  • Antimicrob Agents Chemother. 2015 Mar;59(3):1455-65. doi: 10.1128/AAC.04347-14.
Christopher P Locher 1 Steven M Jones 2 Brian L Hanzelka 2 Emanuele Perola 2 Carolyn M Shoen 3 Michael H Cynamon 3 Andile H Ngwane 4 Ian J Wiid 4 Paul D van Helden 4 Fabrice Betoudji 5 Eric L Nuermberger 5 John A Thomson 2
Affiliations

Affiliations

  • 1 Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA Christopher_locher@hotmail.com.
  • 2 Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
  • 3 Central New York Research Corporation, Syracuse, New York, USA.
  • 4 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.
  • 5 Center for Tuberculosis Research, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
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.

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