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MprF is responsible for the lysinylation of phosphatidylglycerol (PG) to synthesize the positively charged phospholipid (PL) species, lysyl-PG (L-PG). It has been proposed that the single-nucleotide polymorphisms (SNPs) within themprF open reading frame (ORF) are associated with a gain-in-function phenotype in terms of daptomycin resistance inStaphylococcus aureus . (Note that although the official term is daptomycin nonsusceptibility, we use the term daptomycin resistance in this paper for ease of presentation.) Using 22 daptomycin-susceptible (DAPs )/daptomycin-resistant (DAPr ) clinical methicillin-resistantS. aureus (MRSA) strain pairs, we assessed (i) the frequencies and distribution of putativemprF gain-in-function SNPs, (ii) the relationships of the SNPs to both daptomycin resistance and cross-resistance to the prototypical endovascular host defense peptide (HDP) thrombin-induced platelet microbicidal protein (tPMP), and (iii) the impact ofmprF SNPs on positive surface charge phenotype and modifications of membrane PL profiles. Most of themprF SNPs identified in our DAPr strains were clustered within the two MprF loci, (i) the central bifunctional domain and (ii) the C-terminal synthase domain. Moreover, we were able to correlate the presence and location ofmprF SNPs in DAPr strains with HDP cross-resistance, positive surface charge, and L-PG profiles. Although DAPr strains withmprF SNPs in the bifunctional domain showed higher resistance to tPMPs than DAPr strains with SNPs in the synthase domain, this relationship was not observed in positive surface charge assays. These results demonstrated that both charge-mediated and -unrelated mechanisms are involved in DAP resistance and HDP cross-resistance inS. aureus .

antimicrobial agents and chemotherapy

Frequency and Distribution of Single-Nucleotide Polymorphisms within <i>mprF</i> in Methicillin-Resistant Staphylococcus aureus Clinical Isolates and Their Role in Cross-Resistance to Daptomycin and Host Defense Antimicrobial Peptides

Frequency and Distribution of Single-Nucleotide Polymorphisms within mprF in Methicillin-Resistant Staphylococcus aureus Clinical Isolates and Their Role in Cross-Resistance to Daptomycin and Host Defense Antimicrobial Peptides