Pathways of bacterial energy metabolism, such as the proton motive force (PMF), have largely remained unexplored as drug targets, owing to toxicity concerns. Here, we elaborate on a methodical and systematic approach for targeting the PMF using chemical combinations. We began with a high-throughput screen to identify molecules that selectively dissipate either component of the PMF, ΔΨ or ΔpH, in Staphylococcus aureus. We uncovered six perturbants of PMF, three that countered ΔΨ and three that selectively dissipated ΔpH. Combinations of dissipators of ΔΨ with dissipators of ΔpH were highly synergistic against methicillin-resistant S. aureus. Cytotoxicity analyses on mammalian cells revealed that the dose-sparing effect of the observed synergies could significantly reduce toxicity. The discovery and combination of modulators of ΔΨ and ΔpH may represent a promising strategy for combating microbial pathogens.
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