Molecular mechanisms of collateral sensitivity to the antibiotic nitrofurantoin

PLoS Biol. 2020 Jan 27;18(1):e3000612. doi: 10.1371/journal.pbio.3000612. eCollection 2020 Jan.

Abstract

Antibiotic resistance increasingly limits the success of antibiotic treatments, and physicians require new ways to achieve efficient treatment despite resistance. Resistance mechanisms against a specific antibiotic class frequently confer increased susceptibility to other antibiotic classes, a phenomenon designated collateral sensitivity (CS). An informed switch of antibiotic may thus enable the efficient treatment of resistant strains. CS occurs in many pathogens, but the mechanisms that generate hypersusceptibility are largely unknown. We identified several molecular mechanisms of CS against the antibiotic nitrofurantoin (NIT). Mutants that are resistant against tigecycline (tetracycline), mecillinam (β-lactam), and protamine (antimicrobial peptide) all show CS against NIT. Their hypersusceptibility is explained by the overexpression of nitroreductase enzymes combined with increased drug uptake rates, or increased drug toxicity. Increased toxicity occurs through interference of the native drug-response system for NIT, the SOS response, with growth. A mechanistic understanding of CS will help to develop drug switches that combat resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activation, Metabolic / drug effects
  • Activation, Metabolic / genetics
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology
  • Drug Collateral Sensitivity / genetics*
  • Drug Resistance, Bacterial / drug effects
  • Drug Resistance, Bacterial / genetics
  • Escherichia coli / drug effects
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression Regulation, Bacterial / drug effects
  • Microbial Sensitivity Tests
  • Mutation / drug effects
  • Nitrofurantoin / pharmacokinetics
  • Nitrofurantoin / pharmacology*
  • Organisms, Genetically Modified
  • Prodrugs / pharmacokinetics
  • Salmonella enterica / drug effects
  • Salmonella enterica / genetics
  • Salmonella enterica / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • Anti-Bacterial Agents
  • Prodrugs
  • Nitrofurantoin

Grant support

This research was funded by the Swedish Research Council (VR grant 2017-01527 to DIA) and the European Joint Programming Initiative on Antimicrobial Resistance (JPIAMR grant 2016-06480) to DIA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.