(640b) Cellular Proton Motive Force: A Therapeutic Target for Eradicating Methicillin-Resistant Staphylococcus Aureus Persister Cells

Persister cells are a small fraction of non-proliferating variants in a cell population that can tolerate lethal doses of antibiotics. These cells can resume their growth upon removal of antibiotics. In this study, we aim to identify therapeutic strategies to eliminate persister cells of Methicillin-resistant Staphylococcus aureus (MRSA) strains. MRSA remains one of the main virulent pathogens responsible for serious hospital-acquired infections including bloodstream infections and ventilator-associated pneumonia¹. Because of their emerging resistance to some of the major classes of antibiotics, it is becoming increasingly difficult to eradicate MRSA persisters. Although previous studies have shown the effectiveness of proton motive force (PMF) inhibitors at eradicating bacterial cell population ^2,3, further research is needed to investigate the antipersister potency of PMF inhibitors. Using two different MRSA strains and known PMF inhibitors and conventional antibiotics, we showed that anti-persister potency of the inhibitors depends on their ability to disrupt PMF and permeabilize cell membranes (Figure 1). To verify this observed correlation, we screened a small library containing chemicals that can inhibit various electron transport chain complexes and identified several drugs, such as nordihydroguaiaretic acid, gossypol, trifluoperazine, and amitriptyline, that strongly disrupted PMF in MRSA cells by dissipating either the transmembrane electric potential or the proton gradient. These identified inhibitors permeabilized cell membranes and reduced persister levels below the limit of detection. Overall, our study demonstrated that the PMF inhibitors can be highly effective bactericidal drugs with the potential to eradicate persister cells.

References:

1. Enright, M. C. et al. The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA). Proc Natl Acad Sci U S A 99, 7687–7692 (2002).
2. Farha, M. A., Verschoor, C. P., Bowdish, D. & Brown, E. D. Collapsing the proton motive force to identify synergistic combinations against staphylococcus aureus. Chemistry and Biology 20, 1168–1178 (2013).
3. Stokes, J. M. et al. A Deep Learning Approach to Antibiotic Discovery. Cell 180, 688-702.e13 (2020).