TY - JOUR
T1 - Interference with Lipoprotein Maturation Sensitizes Methicillin-Resistant Staphylococcus aureus to Human Group IIA-Secreted Phospholipase A2and Daptomycin
AU - Kuijk, Marieke M
AU - Wu, Yongzheng
AU - van Hensbergen, Vincent P
AU - Shanlitourk, Gizem
AU - Payré, Christine
AU - Lambeau, Gérard
AU - Man-Bovenkerk, Sandra
AU - Herrmann, Jennifer
AU - Müller, Rolf
AU - van Strijp, Jos A G
AU - Pannekoek, Yvonne
AU - Touqui, Lhousseine
AU - van Sorge, Nina M
N1 - Funding Information:
This work was supported by grants to Gérard Lambeau from the Centre National de la Recherche Scientifique (CNRS), the Fondation Jean Valade/Fondation de France (Award FJV_FDF-00112090), the National Research Agency (grants MNaims (ANR-17-CE17-0012-01), AirMN (ANR-20-CE14-0024-01)) and “Investments for the Future” Laboratory of Excellence SIGNALIFE, a network for innovation on signal transduction pathways in life sciences (ANR-11-LABX-0028-01 and ANR-15-IDEX-01), and the Fondation de la Recherche Médicale (DEQ20180339193L) and were used in relation to hGIIA experiments. Part of this work was supported by “Fondation Air Liquide” (Grant: S-CM19006) granted to Lhousseine Touqui to perform studies focused on the role of hGIIA in mouse survival. This study was supported by project 91713303 of the Vidi research program to Nina M. van Sorge and Vincent P. van Hensbergen and 09150181910001 of the Vici research program to Nina M. van Sorge and Marieke M. Kuijk, which is financed by the Dutch Research Council (NWO) to perform all other experiments. None of the sponsors was involved in the design, analysis, interpretation, or preparation of the data presented in the manuscript.
Publisher Copyright:
© 2022 S. Karger AG. All rights reserved.
PY - 2022
Y1 - 2022
N2 - 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 A 2 (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.
AB - 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 A 2 (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.
UR - https://www.scopus.com/pages/publications/85144521650
U2 - 10.1159/000527549
DO - 10.1159/000527549
M3 - Article
C2 - 36473432
SN - 1662-811X
SP - 1
EP - 18
JO - Journal of innate immunity
JF - Journal of innate immunity
ER -
SDG 3 Good Health and Well-being