MmpL3 inhibitors as antituberculosis drugs

Eur J Med Chem. 2020 Aug 15;200:112390. doi: 10.1016/j.ejmech.2020.112390. Epub 2020 May 4.

Abstract

The mycobacterial membrane protein Large 3 (MmpL3) is an inner membrane protein that transports trehalose-monomycolates, precursors for trehalose-dimycolates and mycolic acids that make up essential components of the mycobacterial outer membrane. Inhibition of MmpL3 weakens the mycobacterial cell wall and ultimately results in cell death in both in vitro and in vivo infection models. This highlights the therapeutic potential of MmpL3 as a drug target. High-throughput whole-cell screening along with whole genome sequencing of resistant mutants has identified numerous classes of compounds that can be classified as MmpL3 inhibitors. In this review, we provide insights into the current development of various MmpL3 inhibitors and discuss the potential challenges in this area.

Keywords: Antituberculosis drug; Drug design; MmpL3 inhibitor; SAR.

Publication types

  • Review

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Cell Wall / drug effects*
  • Cord Factors / metabolism
  • Humans
  • Membrane Transport Proteins / metabolism
  • Mycobacterium tuberculosis / drug effects
  • Mycolic Acids / metabolism

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Cord Factors
  • Membrane Transport Proteins
  • MmpL3 protein, Mycobacterium tuberculosis
  • Mycolic Acids
  • trehalose monomycolate