Interference with Lipoprotein Maturation Sensitizes Methicillin-Resistant < b > < i > Staphylococcus aureus < /i > < /b > to Human Group IIA-Secreted Phospholipase A < sub > 2 < /sub > and Daptomycin

Methicillin-resistantStaphylococcus aureus (MRSA) has been classified as a high priority pathogen by the World Health Organization underlining the high demand for new therapeutics to treat infections. Human group IIA-secreted phospholipase A2 (hGIIA) is among the most potent bactericidal proteins against Gram-positive bacteria, includingS. aureus. To determine hGIIA-resistance mechanisms of MRSA, we screened the Nebraska Transposon Mutant Library using a sublethal concentration of recombinant hGIIA. We identified and confirmed the role oflspA, encoding the lipoprotein signal peptidase LspA, as a new hGIIA resistance gene in both in vitro assays and an infection model in hGIIA-transgenic mice. Increased susceptibility of thelspA mutant was associated with enhanced activity of hGIIA on the cell membrane. Moreover,lspA deletion increased susceptibility to daptomycin, a last-resort antibiotic to treat MRSA infections. MRSA wild type could be sensitized to hGIIA and daptomycin killing through exposure to LspA-specific inhibitors globomycin and myxovirescin A1. Analysis of #x3e;26,000S. aureus genomes showed that LspA is highly sequence-conserved, suggesting universal application of LspA inhibition. The role of LspA in hGIIA resistance was not restricted to MRSA sinceStreptococcus mutans andEnterococcus faecalis were also more hGIIA-susceptible afterlspA deletion or LspA inhibition, respectively. Overall, our data suggest that pharmacological interference with LspA may disarm Gram-...
Source: Journal of Innate Immunity - Category: Allergy & Immunology Source Type: research