Targeting bacterial energetics to produce new antimicrobials

Drug Resist Updat. 2018 Jan;36:1-12. doi: 10.1016/j.drup.2017.11.001. Epub 2017 Nov 11.

Abstract

From the war on drug resistance, through cancer biology, even to agricultural and environmental protection: there is a huge demand for rapid and effective solutions to control infections and diseases. The development of small molecule inhibitors was once an accepted "one-size fits all" approach to these varied problems, but persistence and resistance threaten to return society to a pre-antibiotic era. Only five essential cellular targets in bacteria have been developed for the majority of our clinically-relevant antibiotics. These include: cell wall synthesis, cell membrane function, protein and nucleic acid biosynthesis, and antimetabolites. Many of these targets are now compromised through rapidly spreading antimicrobial resistance and the need to target non-replicating cells (persisters). Recently, an unprecedented medical breakthrough was achieved by the FDA approval of the drug bedaquiline (BDQ, trade name Sirturo) for the treatment of multidrug-resistant tuberculosis disease. BDQ targets the membrane-bound F1Fo-ATP synthase, validating cellular energy generating machinery as a new target space for drug discovery. Recently, BDQ and several other FDA-approved drugs have been demonstrated to be respiratory "uncouplers" disrupting transmembrane electrochemical gradients, in addition to binding to enzyme targets. In this review, we summarize the role of bioenergetic systems in mycobacterial persistence and discuss the multi-targeting nature of uncouplers and the place these molecules may have in future drug development.

Keywords: Antimicrobials; Bacteria; Bioenergetics; Drug discovery; Respiration.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use
  • Bacterial Proteins / antagonists & inhibitors*
  • Cell Membrane / drug effects
  • Cell Membrane / physiology
  • Diarylquinolines / pharmacology
  • Diarylquinolines / therapeutic use
  • Drug Design
  • Drug Discovery / methods
  • Drug Resistance, Multiple, Bacterial
  • Electron Transport Complex I
  • Energy Metabolism / drug effects*
  • Humans
  • Membrane Potentials / drug effects
  • Molecular Targeted Therapy / methods
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / physiology*
  • Proton-Translocating ATPases / antagonists & inhibitors
  • Tuberculosis, Multidrug-Resistant / drug therapy*
  • Tuberculosis, Multidrug-Resistant / microbiology
  • Uncoupling Agents / pharmacology
  • Uncoupling Agents / therapeutic use

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Diarylquinolines
  • Uncoupling Agents
  • bedaquiline
  • Proton-Translocating ATPases
  • Electron Transport Complex I