Interventions on Metabolism: Making Antibiotic-Susceptible Bacteria

Abstract

Antibiotics act on bacterial metabolism, and antibiotic resistance involves changes in this metabolism. Interventions on metabolism with drugs might therefore modify drug susceptibility and drug resistance. In their recent article, Martin Vestergaard et al. (mBio 8:e01114-17, 2017, https://doi.org/10.1128/mBio.01114-17) illustrate the possibility of converting intrinsically resistant bacteria into susceptible ones. They reported that inhibition of a central metabolic enzyme, ATP synthase, allows otherwise ineffective polymyxin antibiotics to act on Staphylococcus aureus The study of the intrinsic resistome of bacterial pathogens has shown that several metabolic genes, including multigene transcriptional regulators, contribute to antibiotic resistance. In some cases, these genes only marginally increase antibiotic resistance, but reduced levels of susceptibility might be critical in the evolution or resistance under low antibiotic concentrations or in the clinical response of highly resistant bacteria. Drug interventions on bacterial metabolism might constitute a critical adjuvant therapy in combination with antibiotics to ensure susceptibility of pathogens with intrinsic or acquired antimicrobial resistance.

Keywords: antibiotic resistance; bacterial metabolism; polymyxins; recovering susceptibility.

FIG 1

Low-level resistance mechanisms (2 to 4× MIC), including low-level intrinsic resistance, might be relevant in the early evolution of resistance, allowing bacteria to persist in the presence of low antibiotic concentrations and providing them the opportunity of evolving toward more effective resistance. Also, when canonical specific mechanisms of resistance are surpassed by high concentrations of antibiotics, the 2- to 4× MIC increases provided by “low-level mechanisms” might be critical to produce therapeutic failure.