title: 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.
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 (DAP(s))/daptomycin-resistant (DAP(r)) 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 DAP(r) 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 DAP(r) strains with HDP cross-resistance, positive surface charge, and L-PG profiles. Although DAP(r) strains with mprF SNPs in the bifunctional domain showed higher resistance to tPMPs than DAP(r) 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 in S. aureus.
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA The David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Bayer
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA The David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Nagendra N
authors.initials: NN
authors.lastname: Mishra
authors.affiliation: Public Health Research Institute, Rutgers University, Newark, New Jersey, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Public Health Research Institute, Rutgers University, Newark, New Jersey, USA.
authors.forename: Barry N
authors.initials: BN
authors.lastname: Kreiswirth
authors.affiliation: Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
authors.forename: Aileen
authors.initials: A
authors.lastname: Rubio
authors.affiliation: Department of Animal Science and Technology, Chung-Ang University, Daedeok-myeon, Anseong-si, Gyeonggi-do, Republic of Korea soojin@cau.ac.kr.
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Yang
mesh_terms: D019881:Aminoacyltransferases / Q000235:genetics*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D017576:Daptomycin / Q000494:pharmacology*; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics; D006801:Humans; D008712:Methicillin / Q000494:pharmacology*; D016106:Methicillin Resistance / Q000235:genetics; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000235:genetics*; D008826:Microbial Sensitivity Tests / Q000379:methods; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013203:Staphylococcal Infections / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D019881:Aminoacyltransferases; C429146:mprF protein, Staphylococcus aureus; D017576:Daptomycin; D008712:Methicillin