A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

Abstract

ABSTRACTNew 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 ofMycobacterium tuberculosisin 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 micein vivo. VXc-486 is active against drug-resistant isolates, has bactericidal activity, and kills intracellular and dormantM. tuberculosisbacteria in a low-oxygen environment. Furthermore, we found that VXc-486 inhibits the growth of multiple strains ofMycobacterium abscessus,Mycobacterium aviumcomplex, andMycobacterium kansasii(MICs of 0.1 to 2.0 μg/ml), as well as that of several strains ofNocardiaspp. (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 ofM. tuberculosisthan did VXc-486in vivo. In combination with other antimycobacterial drugs, the prodrug of VXc-486 sterilizedM. tuberculosisinfection 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.