Insights into the mechanisms underlying cell wall-active agents and gentamicin bactericidal synergism against Enterococcus faecalis
Paul Ugalde Silva, Charlene Desbonnet, Louis B Rice, Mónica García-SolacheAbstract
Background
Enterococcus faecalis is a common cause of healthcare-associated infections. They characteristically exhibit reduced susceptibility to penicillins and elevated MICs for aminoglycosides, limiting these drugs as single-agent therapies. Combinations of cell wall synthesis inhibitors and aminoglycosides have a synergistic effect, resulting in bactericidal activity. The mechanism behind this synergism is not fully understood.
Objectives
The present study was performed to explore the relationship between synergistic activity between cell wall-active agents/aminoglycoside combinations and cell membrane energetics in E. faecalis.
Methods
Analysis was performed using reference broth microdilution MIC testing, checkerboard assays, time–kill assays and fluorescent microscopy.
Results
We observed that cell wall remodelling agents promoted aminoglycoside uptake facilitated by antibiotic-induced decreases in the intracellular pH (pHi).
Conclusions
Drugs that inhibit cell wall synthesis induce a decrease in the pHi, suggesting that cell wall remodelling is linked to ion transport and cytoplasmic acidification. Our study supports a model in which inhibition of peptidoglycan synthesis produces membrane stress-associated intracellular acidification that promotes ΔpH-dependent aminoglycoside uptake in E. faecalis