Pentamidine sensitizes FDA-approved non-antibiotics for the inhibition of multidrug-resistant Gram-negative pathogens

Eur J Clin Microbiol Infect Dis. 2020 Sep;39(9):1771-1779. doi: 10.1007/s10096-020-03881-0. Epub 2020 Apr 2.

Abstract

Pentamidine sensitizes FDA-approved antibiotics to combat Gram-negative pathogens. We screened 1374 FDA-approved non-antibiotics for their ability to be sensitized by pentamidine against Escherichia coli. We identified mitomycin C and mefloquine as potent hits effective against multiple drug-resistant, Gram-negative bacteria. Killing kinetics and an in vivo model with Caenorhabditis elegans (C. elegans) revealed that such combinations produced synergy against colistin-resistant Enterobacter cloacae (E. cloacae). These findings suggest combinations of FDA-approved non-antibiotics, and pentamidine can be repurposed into new antimicrobial agents.

Keywords: Drug repurposing; Gram-negative pathogens; Non-antibiotics; Pentamidine; Sensitizer.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Caenorhabditis elegans / drug effects
  • Drug Repositioning
  • Drug Resistance, Multiple, Bacterial
  • Drug Synergism
  • Drug Therapy, Combination
  • Enterobacter cloacae / drug effects
  • Gram-Negative Bacteria / drug effects*
  • Gram-Negative Bacterial Infections / drug therapy*
  • Gram-Negative Bacterial Infections / microbiology
  • Humans
  • Microbial Sensitivity Tests
  • Models, Animal
  • Pentamidine / administration & dosage
  • Pentamidine / pharmacology*
  • Pentamidine / therapeutic use
  • United States
  • United States Food and Drug Administration

Substances

  • Anti-Bacterial Agents
  • Pentamidine