ANALYSIS OF MYCOBACTERIAL CELL ENVELOPE STRESS AND DISCOVERY OF A NOVEL MMPL3 INHIBITOR

Abstract

The bottleneck in developing new drugs for tuberculosis is the lack of attractive targets with their associated whole-cell active lead compounds. To address this issue, we employed a pathway-based whole-cell screening approach and identified a novel bactericidal anti-mycobacterial acetamide, E11. Whole genome sequencing of the E11 resistant mutants revealed mycolic acid transporter MmpL3 as the probable target, which was confirmed by biochemical analyses. Future work involves lead optimization studies.

In a concurrent project we attempted to understand physiological alterations in mycobacteria on exposure to cell wall targeting drugs. Here, we showed that treatment of mycobacteria with cell wall inhibitors caused a burst in intrabacterial ATP concentration, which could be suppressed by co-treatment with oxidative phosphorylation inhibitors. Interestingly, suppression of the drug induced ATP surge attenuated bactericidal activity of the cell wall inhibitors and abrogated promoter activity of the cell envelope stress response operon iniBAC. Identification of the molecular mechanisms linking these processes may reveal novel targets for the discovery of bactericidal antibiotics.