Proton Motive Force Inhibitors Are Detrimental To Methicillin-Resistant Staphylococcus Aureus Persister Cells

Methicillin-resistant Staphylococcus aureus (MRSA) strains are resistant to conventional antibiotics. These pathogens can form persister cells, which are transiently tolerant to bactericidal antibiotics, making them extremely dangerous. Previous studies have shown the effectiveness of proton motive force (PMF) inhibitors at killing bacterial cells; however, whether these agents can launch a new treatment strategy to eliminate persister cells mandates further investigation. Here, using known PMF inhibitors and two different MRSA isolates, we showed that antipersister potency of PMF inhibitors seemed to correlate with their ability to disrupt PMF and permeabilize cell membranes. By screening a small chemical library to verify this correlation, we identified a subset of chemicals (including nordihydroguaiaretic acid, gossypol, trifluoperazine, and amitriptyline) that strongly disrupted PMF in MRSA cells by dissipating either the transmembrane electric potential ({Delta}{Psi}) or the proton gradient ({Delta}pH). These drugs robustly permeabilized cell membranes and reduced persister levels below the limit of detection. Overall, our study further highlights the importance of cellular PMF as a target for designing new antipersister therapeutics.