Abstract
Latent tuberculosis infection is caused by Mycobacterium tuberculosis (Mtb) persistence and poses a significant challenge to the eradication of tuberculosis. The detection of Mtb DevR/DosR dormancy regulon expression in clinical specimens has provided evidence for the existence of persistent/dormant tubercle bacilli in vivo. Targeting of DevR is expected to eliminate these persisters that are tolerant to anti-tubercular drugs. The presence of redundant pathways of DevR activation in Mtb necessitates targeting DevR, and not its cognate sensor kinases, DevS and DosT. Drug discovery programs are heavily dependent on inhibitor screening assays. Here, we report a high throughput screening assay in Mtb termed ReFPA (Real Time Fluorescence Plate Assay) to identify inhibitors that specifically target DevR. Using ReFPA, we identified novel thiazolidin-4-one-based inhibitors of DevR, namely N5, N6 and N11, that interfered with the hypoxic viability of Mycobacterium bovis BCG and were non-toxic to HepG2 cells. In silico docking analysis revealed that N5, N6 and N11 bound to a common pocket located in the C-terminal domain of DevR. The interaction of N5, N6 and N11 with DevR was experimentally confirmed using thermal shift assay. These findings demonstrate the identification of a new and promising scaffold to design anti-DevR molecules for intercepting mycobacterial dormancy.
Published Version
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