PBP4 is required for serum-induced cell wall thickening and antibiotic tolerance in Staphylococcus aureus

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The bacterial pathogen Staphylococcus aureus responds to the host environment by synthesising a thick peptidoglycan cell wall which protects the bacterium from membrane-targeting antimicrobials and the immune response. However, the proteins required for this response were previously unknown. Here, we demonstrate by three independent approaches that the penicillin binding protein PBP4 is crucial for serum-induced cell wall thickening. Firstly, mutants lacking various non-essential cell wall synthesis enzymes were tested, revealing that a mutant lacking pbp4 was unable to generate a thick cell wall in serum. This resulted in reduced serum-induced tolerance of the pbp4 mutant towards the last resort antibiotic daptomycin relative to wildtype cells. Secondly, we found that serum-induced cell wall thickening occurred in each of a panel of 134 clinical bacteraemia isolates, except for one strain with a naturally-occurring mutation that confers a S140R substitution in the active site of PBP4. Finally, inhibition of PBP4 with cefoxitin prevented serum-induced cell wall thickening and the resulting antibiotic tolerance in the USA300 strain and in clinical MRSA isolates. Together, this provides a rationale for combining daptomycin with cefoxitin, a PBP4 inhibitor, to potentially improve treatment outcomes for patients with invasive MRSA infections.

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  1. Thank you for your hard work on this paper! Antibiotic resistance is a critical problem in our society and we need more research that could lead to better antibiotic treatments. I studied the Staphylococcus aureus PBP4 enzyme while I was pursuing my postdoc in the VanNieuwenhze lab at Indiana University. I was amazed at its promiscuity and its ability to use as substrates a variety of different D-amino acid dyes that the chemists in the lab were preparing. I was wondering if you have any more information, or ideas, about how it may contribute to the thickening of the cell wall? Is the expression of PBP4 increased during incubation with serum? Is the in vivo activity of PBP4 somehow augmented by serum? Or is the increase in cell wall thickness just a result of the slowing down of cell wall hydrolysis when the bacteria are grown in serum? Thank you for your time!