Adjunctive therapy for multidrug-resistant bacterial infections: Type III secretion system and efflux inhibitors

Drug Discov Today. 2021 Sep;26(9):2173-2181. doi: 10.1016/j.drudis.2021.03.031. Epub 2021 Apr 9.

Abstract

The increasing prevalence of multidrug-resistant (MDR) bacterial infections has created a crucial need for new therapeutics that avoid or minimize existing resistance mechanisms. In this review, we describe the development of novel classes of small-molecule adjunctive agents targeting either a bacterial virulence factor, the Pseudomonas aeruginosa type III secretion system (T3SS), or an intrinsic resistance factor, resistance-nodulation-cell division superfamily (RND) efflux pumps of the Enterobacteriaceae. These agents are designed to be administered with antibacterials to improve their efficacy. T3SS inhibition rescues host innate immune system cells from injection with bacterial toxins, whereas RND efflux pump inhibition increases antibiotic susceptibility, in both cases improving the efficacy of the combined antibacterial.

Keywords: Adjunctive therapy; Anti-virulence; Efflux pump inhibitor; Enterobacteriaceae; P. aeruginosa; Type III secretion.

Publication types

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

MeSH terms

  • Animals
  • Anti-Bacterial Agents / therapeutic use*
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Gram-Negative Bacterial Infections / drug therapy*
  • Humans
  • Membrane Transport Proteins / metabolism*
  • Type III Secretion Systems / antagonists & inhibitors*
  • Type III Secretion Systems / metabolism

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Membrane Transport Proteins
  • Type III Secretion Systems