Resistance against Membrane-Inserting MmpL3 Inhibitor through Upregulation of MmpL5 in Mycobacterium tuberculosis

Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01100-20. doi: 10.1128/AAC.01100-20. Print 2020 Nov 17.

Abstract

Spiroketal indolyl Mannich bases (SIMBs) present a novel class of membrane-inserting antimycobacterials with efficacy in a tuberculosis mouse model. SIMBs exert their antibacterial activity by two mechanisms. The indolyl Mannich base scaffold causes permeabilization of bacteria, and the spiroketal moiety contributes to inhibition of the mycolic acid transporter MmpL3. Here, we show that low-level resistance to SIMBs arises by mutations in the transcriptional repressor MmpR5, resulting in upregulation of the efflux pump MmpL5.

Keywords: MmpL3; MmpL5; MmpR5; indolyl Mannich bases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology
  • Antitubercular Agents / therapeutic use
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Membrane Transport Proteins
  • Mice
  • Mycobacterium tuberculosis* / metabolism
  • Mycolic Acids
  • Up-Regulation* / drug effects

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Membrane Transport Proteins
  • Mycolic Acids