Antimicrobial resistance (AMR) is one of the greatest current threats to human health. Staphylococcus aureus shows resistance to all licensed anti-staphylococcal drugs and up to 20% of patients infected with methicillin resistant S. aureus (MRSA) die from systemic infections. This problem is compounded by the ability of S. aureus to produce phenotypic variants called persisters, which are highly tolerant to antibiotic killing and are implicated in chronic infections and antibiotic treatment failures. Unpublished research in our laboratory using in vivo models of invasive pneumonia and sepsis demonstrated that exposure to oxacillin sensitised stationary phase MRSA persisters to killing by vancomycin. This sensitisation of persisters correlated with oxacillin-induced upregulation of numerous proteins involved in cell wall biosynthesis to levels measured in exponential phase bacteria, which were also susceptible to vancomycin. These findings support the inclusion of b-lactam antibiotics in the treatment regime for patients with MRSA infections, as an adjunct anti-virulence and anti-persister therapy, which would represent an important change to current clinical practice with the potential to significantly improve patient outcomes in a cost effective manner. However, it is unknown whether these data are relevant to S. epidermidis, which is also an important pathogen in hospital patients with implanted medical devices. Indeed there is liitle data on the role of persister cells in S. epidermidis. In this proposed research project, the production of persister cells by S. epidermidis will be examined and the capacity of b-lactam / vancomycin combinations to kill these cells will be determined.
