The Journal of infectious diseases · 2025
Phage-Encoded Virulence Factor, Gp05, Alters Membrane Phospholipids and Reduces Antimicrobial Susceptibility in Methicillin-Resistant Staphylococcus aureus.
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Li Yi, Mishra Nagendra N, Chen Liang, Manna Adhar C, Cheung Ambrose L, Proctor Richard A, Xiong Yan Q
Аннотация
BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of endovascular infections. The prophage-encoded protein Gp05 has been identified as a critical virulence factor that contributes to MRSA persistence during vancomycin treatment in an experimental endocarditis model. However, the mechanisms underlying this persistence phenotype remain poorly understood.
METHODS: This study investigated the genetic factors contributing to Gp05-associated MRSA persistence utilizing RNA sequencing (RNA-seq) on an isogenic MRSA strain set, including a clinical persistent bacteremia isolate, its chromosomal gp05 deletion mutant, and gp05-complemented strains.
RESULTS: RNA-seq revealed significant downregulation of the GraSR two-component regulatory system and its downstream genes, mprF and dltABCD, in the gp05 deletion mutant compared to the wild-type and gp05-complemented strains. This downregulation led to a substantial shift in membrane phospholipid composition, with an increased phosphatidylglycerol and a corresponding decrease in lysyl-phosphatidylglycerol. These changes resulted in increased susceptibility of the gp05 deletion mutant to human cationic antimicrobial peptide (CAMP) LL-37, neutrophils, and vancomycin. These results were confirmed in an isogenic gp05 overexpression strain set in MRSA JE2 background.
CONCLUSIONS: Gp05 modulates MRSA surface phospholipid components and charge, offering new insights into the molecular mechanisms underlying Gp05-mediated persistence in endovascular infections and potential therapeutic targets to combat these infections.
METHODS: This study investigated the genetic factors contributing to Gp05-associated MRSA persistence utilizing RNA sequencing (RNA-seq) on an isogenic MRSA strain set, including a clinical persistent bacteremia isolate, its chromosomal gp05 deletion mutant, and gp05-complemented strains.
RESULTS: RNA-seq revealed significant downregulation of the GraSR two-component regulatory system and its downstream genes, mprF and dltABCD, in the gp05 deletion mutant compared to the wild-type and gp05-complemented strains. This downregulation led to a substantial shift in membrane phospholipid composition, with an increased phosphatidylglycerol and a corresponding decrease in lysyl-phosphatidylglycerol. These changes resulted in increased susceptibility of the gp05 deletion mutant to human cationic antimicrobial peptide (CAMP) LL-37, neutrophils, and vancomycin. These results were confirmed in an isogenic gp05 overexpression strain set in MRSA JE2 background.
CONCLUSIONS: Gp05 modulates MRSA surface phospholipid components and charge, offering new insights into the molecular mechanisms underlying Gp05-mediated persistence in endovascular infections and potential therapeutic targets to combat these infections.