1. Structure-based design of anti-mycobacterial drug leads that target the mycolic acid transporter MmpL3.
- Author
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Hu T, Yang X, Liu F, Sun S, Xiong Z, Liang J, Yang X, Wang H, Yang X, Guddat LW, Yang H, Rao Z, and Zhang B
- Subjects
- Antitubercular Agents chemistry, Antitubercular Agents pharmacology, Antitubercular Agents therapeutic use, Bacterial Proteins metabolism, Cryoelectron Microscopy, Humans, Membrane Proteins metabolism, Membrane Transport Proteins metabolism, Protons, Mycobacterium tuberculosis metabolism, Mycolic Acids metabolism
- Abstract
New anti-tubercular agents are urgently needed to address the emerging threat of drug resistance to human tuberculosis. Here, we have used structure-assisted methods to develop compounds that target mycobacterial membrane protein large 3 (MmpL3). MmpL3 is essential for the transport of mycolic acids, an important cell-wall component of mycobacteria. We prepared compounds that potently inhibit the growth of Mycobacterium tuberculosis (Mtb) and other mycobacteria in cell culture. The cryoelectron microscopy (cryo-EM) structure of mycobacterial MmpL3 in complex with one of these compounds (ST004) was determined using lipid nanodiscs at an overall resolution of 3.36 Å. The structure reveals the binding mode of ST004 to MmpL3, with the S4 and S5 subsites of the inhibitor-binding pocket in the proton translocation channel playing vital roles. These data are a promising starting point for the development of anti-tuberculosis drugs that target MmpL3., Competing Interests: Declaration of interests ShanghaiTech University has applied for a PCT patent that covers all the compounds presented here. All authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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