Abstract

Owing to the rise in drug resistance in
tuberculosis combined with the global spread of its causative pathogen, Mycobacterium tuberculosis (Mtb),
innovative anti-mycobacterial agents are urgently needed. To address this
problem, we have employed drug repurposing approach to discover novel
FDA-approved drugs to inhibit Mtb
growth. Here, we have used essential Mtb
enzyme, DNA gyrase, a promising and potential target for novel
anti-tuberculosis chemotherapeutics. High-throughput screening of compounds
(using FDA-compounds library) was done against the active site of Mtb DNA gyrase, the region of ATP
binding (N-terminal domain) pocket on gyrase B subunit. Here, we identified
total of 4 compounds (Doxorubicin, Epirubicin, Idarubicin, Terlipressin)
tightly binds to ATPase binding pocket of N-terminal domain of gyrase B (MtbGyrB47). We investigated both
inhibition of Mtb DNA gyrase and the
inhibitory activity against in vitro
growth of Mtb and M. smegmatis (Msm) by FDA-drugs. Among
which, doxorubicin, an anthracycline antibiotic (used as an anticancer drug),
was found to be a potent inhibitor of Mtb
DNA gyrase. Low-μM inhibition of Mtb
DNA gyrase was correlated with their low-μM minimum inhibitory concentrations
for all screened FDA-drugs. Doxorubicin exhibited IC₅₀ value of
0.6±0.14 µM against MtbGyrB47, kD
values of 0.06±0.21 µM and MIC₉₀ values of 0.12 µg/ml. Our results
strongly suggests that the screened compounds (anthracyclines) target
mycobacterial DNA gyarse, inhibits gyrase catalytic cycle and retard Mtb growth. Hence, anthracyclines
inhibitors of Gyrase B exhibit many of the characteristics required for their
consideration as a potential front-line antimycobacterial therapeutic.