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

Arnold S. Bayer, Nagendra N. Mishra, Liang Chen, Barry N. Kreiswirth, Aileen Rubio, Soo Jin Yang

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

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 the mprF open reading frame (ORF) are associated with a gain-in-function phenotype in terms of daptomycin resistance in Staphylococcus 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-resistant S. aureus (MRSA) strain pairs, we assessed (i) the frequencies and distribution of putative mprF 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 of mprF SNPs on positive surface charge phenotype and modifications of membrane PL profiles. Most of the mprF 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 of mprF SNPs in DAPr strains with HDP cross-resistance, positive surface charge, and L-PG profiles. Although DAPr strains with mprF SNPs in the bifunctional domain showed higher resistance to tPMPs than DAPrstrains 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 in S. aureus.

Original languageEnglish (US)
Pages (from-to)4930-4937
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume59
Issue number8
DOIs
StatePublished - Aug 1 2015

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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