Tuberculosis (TB) is an important infectious disease threat worldwide. HIV coinfection/immunosuppression and widespread drug resistance contributes to the challenge of controlling TB. TB resulted from Mycobacterium tuberculosis. It is a slow-growing, acid-fast bacillus that withstands a harsh immunological assault by human host macrophages and effector cells, as well as suboptimal chemotherapy, by persisting in a semi-dormant state of replication. New drugs are urgently needed to shorten the treatment regimen and to more effectively treat drug-sensitive and, especially, drug-resistant M. tuberculosis infections. A study from Christopher P. Locher discovered and identified a potent Gyrase B inhibitor, VXc-486 as a preclinical candidate drug for TB.

Especially, DNA gyrase and topoisomerase IV represent two clinically validated drug targets for bacterial infections. They are essential for DNA replication. Furthermore, several different chemical classes have been described as inhibitors of gyrase B with potent activity against DR bacteria, including M. tuberculosis.

VXc-486 is a gyrase B inhibitor, with bactericidal activity. Likewise, VXc-486 potently inhibits multiple drug-sensitive isolates and drug-resistant isolates of Mycobacterium tuberculosis, with MICs of 0.03 to 0.30 μg/mL and 0.08 to 5.48 μg/mL, respectively. VXc-486 reduces mycobacterial burdens in the lungs of infected mice in vivo. Moreover, VXc-486 is active against drug-resistant isolates 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, as well as that of several strains of Nocardia spp. Besides, 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.

Locher CP, et al. 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.