In:
Journal of Innate Immunity, S. Karger AG
Kurzfassung:
Methicillin-resistant 〈 i 〉 Staphylococcus aureus 〈 /i 〉 (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 A 〈 sub 〉 2 〈 /sub 〉 (hGIIA) is among the most potent bactericidal proteins against Gram-positive bacteria, including 〈 i 〉 S. aureus 〈 /i 〉 . 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 of 〈 i 〉 lspA 〈 /i 〉 , 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 the 〈 i 〉 lspA 〈 /i 〉 mutant was associated with enhanced activity of hGIIA on the cell membrane. Moreover, 〈 i 〉 lspA 〈 /i 〉 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;26,000 〈 i 〉 S. aureus 〈 /i 〉 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 since 〈 i 〉 Streptococcus mutans 〈 /i 〉 and 〈 i 〉 Enterococcus faecalis 〈 /i 〉 were also more hGIIA-susceptible after 〈 i 〉 lspA 〈 /i 〉 deletion or LspA inhibition, respectively. Overall, our data suggest that pharmacological interference with LspA may disarm Gram-positive pathogens, including MRSA, to enhance clearance by innate host defense molecules and clinically applied antibiotics.
Materialart:
Online-Ressource
ISSN:
1662-811X
,
1662-8128
Sprache:
Englisch
Verlag:
S. Karger AG
Publikationsdatum:
2023
ZDB Id:
2455818-7
