Advancements in Tuberculosis and Mycobacterial Infections Treatment: The Role of Gyrase B Inhibitor VXc-486

The development of new treatments for drug-resistant tuberculosis (TB) is critical due to the rising prevalence of strains that are resistant to fluoroquinolones, such as moxifloxacin. VXc-486, a newly discovered aminobenzimidazole, has demonstrated the ability to inhibit both drug-sensitive and drug-resistant isolates of Mycobacterium tuberculosis in vitro with minimal inhibitory concentrations (MICs) ranging from 0.03 to 5.48 μg/ml. This compound targets gyrase B and has shown activity against intracellular and dormant bacteria in low-oxygen conditions, which is crucial for TB treatment.

In vivo studies in mice have shown that VXc-486 can significantly reduce mycobacterial loads in the lungs and has bactericidal effects. The compound has also exhibited inhibitory activity against multiple strains of other Mycobacterium species, including M. abscessus, M. avium complex, and M. kansasii, as well as Nocardia spp.

A phosphate prodrug form of VXc-486 has been found to be more potent in killing M. tuberculosis in vivo compared to the parent compound. When combined with other antimycobacterial drugs, the prodrug has the potential to sterilize M. tuberculosis infections, as demonstrated in a relapse infection study in mice. The prodrug's performance was at least as effective as moxifloxacin, a gyrase A inhibitor.

These results indicate that VXc-486 and its prodrug form are promising candidates for further development as treatments for both tuberculosis and nontuberculous mycobacterial infections, offering new hope for combating the growing issue of drug resistance in these diseases.