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.