Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in Mycobacterium tuberculosis

• DOI: 10.1021/acsinfecdis.0c00675
• Publication Date: 2020-12-15T18:07:44Z
• Authors: Shipra Grover; Curtis A. Engelhart; Esther Pérez-Herrán; Wei Li; Katherine A. Abra...; Kadamba Papavinas...; James M. Bean; Christopher M. Sa...; Alfonso Mendoza-L...; Gurdyal S. Besra; Mary Jackson; Dirk Schnappinger
• Keywords: 0301 basic medicine; 570; Bacterial Infections and Mycoses; Antitubercular Agents; Membrane Transport Proteins; Medicinal-Pharmaceutical Chemistry; Mycobacterium tuberculosis; Pharmacy and Pharmaceutical Sciences; 540; Microbiology; antibiotics; drug discovery; 3. Good health; 03 medical and health sciences; Bacterial Proteins; Mycolic Acids; molecular genetics; mycolic acids; respiration; targeted whole-cell screen

MmpL3, an essential mycolate transporter in the inner membrane of Mycobacterium tuberculosis (Mtb), has been identified as a target multiple, chemically diverse antitubercular drugs. However, several these molecules seem to have secondary targets and inhibit bacterial growth by more than one mechanism. Here, we describe cell-based assay that utilizes two-way regulation MmpL3 expression readily identify MmpL3-specific inhibitors. We successfully used this novel guanidine-based inhibitor from library 220 compounds Mtb largely unknown mechanisms. furthermore inhibitors cytochrome bc1-aa3 oxidase class off-target hits whole-cell screens for report sulfanylacetamide potential QcrB inhibitor.