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Published on: May 15, 2019
Interference with Lipoprotein Maturation Sensitizes Methicillin-Resistant Staphylococcus aureus to Human Group
Marieke M Kuijk1, Yongzheng Wu2, Vincent P van Hensbergen3
1Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The Netherlands, marieke@kuijknet.nl.
Abstract:
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.
Insights
New research reveals that inhibiting lipoprotein signal peptidase A (LspA) can resensitize methicillin-resistant Staphylococcus aureus (MRSA) to host defenses and antibiotics. This finding offers a promising strategy against high-priority MRSA infections.
Area of Science:
- Microbiology and Infectious Diseases
- Drug Discovery and Development
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) is a high-priority pathogen requiring novel therapeutics.
- Human group IIA-secreted phospholipase A2 (hGIIA) exhibits potent bactericidal activity against Gram-positive bacteria, including S. aureus.
Purpose of the Study:
- To identify mechanisms by which MRSA develops resistance to hGIIA.
- To explore LspA as a potential therapeutic target for enhancing MRSA susceptibility.
Main Methods:
- Screening of the Nebraska Transposon Mutant Library for hGIIA resistance genes.
- In vitro assays and infection models in hGIIA-transgenic mice to confirm the role of lspA.
- Analysis of over 26,000 S. aureus genomes for LspA conservation.
- Testing the efficacy of LspA-specific inhibitors (globomycin, myxovirescin A1).
Main Results:
- Lipoprotein signal peptidase A (LspA) was identified as a novel hGIIA resistance gene in MRSA.
- lspA deletion increased MRSA susceptibility to hGIIA and daptomycin, a last-resort antibiotic.
- LspA inhibition sensitized MRSA, Streptococcus mutans, and Enterococcus faecalis to hGIIA and daptomycin.
- LspA is highly conserved across S. aureus strains, indicating broad applicability.
Conclusions:
- Pharmacological inhibition of LspA can disarm Gram-positive pathogens, including MRSA.
- Targeting LspA enhances the efficacy of innate host defense molecules and existing antibiotics.
- LspA inhibition represents a promising strategy to combat challenging Gram-positive bacterial infections.
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