Interference with Lipoprotein Maturation Sensitizes Methicillin-Resistant Staphylococcus aureus to Human Group IIA-Secreted Phospholipase A 2 and Daptomycin

Methicillin-resistant Staphylococcus 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, including S. 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 of lspA, 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 lspA 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 >26,000 S. 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 since Streptococcus mutans and Enterococcus faecalis were also more hGIIA-susceptible after lspA 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.

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch

References and Relationships

• Bibliographic citation: Interference with Lipoprotein Maturation Sensitizes Methicillin-Resistant Staphylococcus aureus to Human Group IIA-Secreted Phospholipase A 2 and Daptomycin ; volume:15 ; number:1 ; year:2022 ; pages:333-350 ; extent:18 ; Journal of innate immunity ; 15, Heft 1 (2022), 333-350 (gesamt 18)

Contributors, Places and Time

• Creator: Kuijk, Marieke M. ; Wu, Yongzheng ; van Hensbergen, Vincent P. ; Shanlitourk, Gizem ; Payré, Christine ; Lambeau, Gérard ; Man-Bovenkerk, Sandra ; Herrmann, Jennifer ; Müller, Rolf ; van Strijp, Jos A.G. ; Pannekoek, Yvonne ; Touqui, Lhousseine ; van Sorge, Nina M.

Further information

• DOI: 10.1159/000527549
• URN: urn:nbn:de:101:1-2024010323541316998977
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:34 AM CEST