2. Academic Validation
  3. Structure-based design of anti-mycobacterial drug leads that target the mycolic acid transporter MmpL3

Structure-based design of anti-mycobacterial drug leads that target the mycolic acid transporter MmpL3

  • Structure. 2022 Oct 6;30(10):1395-1402.e4. doi: 10.1016/j.str.2022.07.009.
Tianyu Hu 1,  Xiaolin Yang 2,  Fengjiang Liu 3,  Shan Sun 2,  Zhiqi Xiong 4,  Jingxi Liang 5,  Xiaobao Yang 2,  Haofeng Wang 2,  Xiuna Yang 6,  Luke W Guddat 7,  Haitao Yang 8,  Zihe Rao 9,  Bing Zhang 10
Affiliations

Affiliations

  • 1 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100101, China.
  • 2 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 3 Innovative Center for Pathogen Research, Guangzhou Laboratory, Guangzhou 510005, China.
  • 4 Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China.
  • 5 State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300353, China.
  • 6 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China.
  • 7 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 8 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China. Electronic address: yanght@shanghaitech.edu.cn.
  • 9 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Innovative Center for Pathogen Research, Guangzhou Laboratory, Guangzhou 510005, China; Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300353, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China. Electronic address: raozh@tsinghua.edu.cn.
  • 10 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China. Electronic address: zhangbing@shanghaitech.edu.cn.
PMID: 35981536 DOI: 10.1016/j.str.2022.07.009
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.

Keywords

MmpL3; Mtb; ST004; drug design; drug target; mycobacteria.

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