Paenipeptin Analogues Potentiate Clarithromycin and Rifampin against mcr-1-Mediated Polymyxin-Resistant Escherichia coli In Vivo

Antimicrob Agents Chemother. 2020 Mar 24;64(4):e02045-19. doi: 10.1128/AAC.02045-19. Print 2020 Mar 24.

Abstract

Polymyxin resistance mediated by the mcr-1 gene threatens the last-resort antibiotics. Linear lipopeptide paenipeptin analogues 1 and 15 disrupted the outer membrane of Gram-negative pathogens and potentiated clarithromycin and rifampin against mcr-1-positive Escherichia coli from the FDA-CDC Antimicrobial Resistance Isolate Bank. In the presence of paenipeptin, clarithromycin and rifampin resulted in over 3-log reduction of E. coliin vitro Moreover, paenipeptin-antibiotic combinations significantly reduced E. coli in a murine thigh infection model.

Keywords: combination therapy; lipopeptide; mcr-1; paenipeptin; potentiator.

Publication types

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

MeSH terms

  • Animals
  • Bacterial Outer Membrane / drug effects
  • Clarithromycin / pharmacology*
  • Drug Resistance, Bacterial / genetics
  • Drug Synergism
  • Drug Therapy, Combination
  • Escherichia coli / drug effects*
  • Escherichia coli / genetics
  • Escherichia coli Infections / drug therapy
  • Escherichia coli Proteins / genetics*
  • Female
  • Mice
  • Polymyxins / pharmacology*
  • Rifampin / pharmacology*

Substances

  • Escherichia coli Proteins
  • MCR-1 protein, E coli
  • Polymyxins
  • Clarithromycin
  • Rifampin