Collapsing the Proton Motive Force to Identify Synergistic Combinations against Staphylococcus aureus

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, Delta Psi or Delta pH, in Staphylococcus aureus. We uncovered six perturbants of PMF, three that countered Delta Psi and three that selectively dissipated Delta pH. Combinations of dissipators of Delta Psi with dissipators of Delta pH 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 Delta Psi and Delta pH may represent a promising strategy for combating microbial pathogens.