Ftsh Sensitizes Methicillin-Resistant to β-Lactam Antibiotics by Degrading YpfP, a Lipoteichoic Acid Synthesis Enzyme.

In the Gram-positive pathogen , FtsH, a membrane-bound metalloprotease, plays a critical role in bacterial virulence and stress resistance. This protease is also known to sensitize methicillin-resistant (MRSA) to β-lactam antibiotics; however, the molecular mechanism is not known. Here, by the analysis of FtsH substrate mutants, we found that FtsH sensitizes MRSA specifically to β-lactams by degrading YpfP, the enzyme synthesizing the anchor molecule for lipoteichoic acid (LTA). Both the overexpression of FtsH and the disruption of -sensitized MRSA to β-lactams were observed. The knockout mutation in and increased the thickness of the cell wall. The β-lactam sensitization coincided with the production of aberrantly large LTA molecules. The combination of three mutations in the , and SAUSA300_2133 genes blocked the β-lactam-sensitizing effect of FtsH. Murine infection with the mutant could be treated by oxacillin, a β-lactam antibiotic ineffective against MRSA; however, the effective concentration of oxacillin differed depending on the strain. Our study demonstrated that the β-lactam sensitizing effect of FtsH is due to its digestion of YpfP. It also suggests that the larger LTA molecules are responsible for the β-lactam sensitization phenotype, and YpfP is a viable target for developing novel anti-MRSA drugs.