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Small Molecule Adjuvants Potentiate Colistin Activity and Attenuate Resistance Development in Escherichia coli by

Dipak Kathayat1, Linto Antony2, Loic Deblais1

  • 1Food Animal Health Research Program, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, OH 44691, USA.

Infection and Drug Resistance
|August 9, 2020
PubMed
Abstract

Insights

Novel small molecules (SMs) potentiate colistin, a last-resort antibiotic, against multi-drug resistant Gram-negative bacteria. These SMs reduce colistin resistance evolution and can be developed as anti-evolution drugs.

Area of Science:

  • Microbiology
  • Pharmacology
  • Drug Discovery

Background:

  • Colistin is a critical antibiotic for treating multi-drug resistant (MDR) Gram-negative bacterial infections.
  • Rising colistin resistance in bacteria from food animals and humans necessitates new therapeutic strategies.
  • Mobile colistin resistance (mcr) genes and chromosomal mutations limit colistin's effectiveness.

Purpose of the Study:

  • To investigate the adjuvant potential of novel small molecules (SMs) in combination with colistin.
  • To evaluate the efficacy of SM-colistin combinations against avian pathogenic Escherichia coli (APEC).
  • To assess the impact of SMs on the evolution of colistin resistance.

Main Methods:

  • Checkerboard assays were used to determine synergistic effects.
  • A wax moth (Galleria mellonella) larval model assessed in vivo efficacy.
  • Whole genome sequencing and gene expression analysis (pmrCAB, pmrH) investigated resistance evolution.

Main Results:

  • SM-colistin combinations synergistically reduced colistin's minimum bactericidal concentration by at least 10-fold.
  • In vivo, combinations enhanced colistin efficacy, improving survival and reducing bacterial load.
  • SMs decreased colistin resistance evolution frequency and downregulated key resistance genes (pmrCAB, pmrH).
  • Novel mutations in pmrB and pmrA were identified in colistin-resistant isolates, but not when SMs were present.

Conclusions:

  • Two SMs (SM2 and SM3) were identified that potentiate colistin activity.
  • These SMs significantly attenuated the development of colistin resistance in APEC.
  • SMs show promise as anti-evolution drugs to preserve colistin's efficacy.
Keywords:
anti-evolution drugcolistinpmrCABpmrHresistancesmall molecules

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