title: Emergence of daptomycin resistance in daptomycin-naïve rabbits with methicillin-resistant Staphylococcus aureus prosthetic joint infection is associated with resistance to host defense cationic peptides and mprF polymorphisms.
abstract: BACKGROUND
  Previous studies of both clinically-derived and in vitro passage-derived daptomycin-resistant (DAP-R) Staphylococcus aureus strains demonstrated the coincident emergence of increased DAP MICs and resistance to host defense cationic peptides (HDP-R).
  
  
  METHODS
  In the present investigation, we studied a parental DAP-susceptible (DAP-S) methicillin-resistant Staphylococcus aureus (MRSA) strain and three isogenic variants with increased DAP MICs which were isolated from both DAP-treated and DAP-untreated rabbits with prosthetic joint infections. These strains were compared for: in vitro susceptibility to distinct HDPs differing in size, structure, and origin; i.e.; thrombin-induced platelet microbicidal proteins [tPMPs] and human neutrophil peptide-1 [hNP-1]; cell membrane (CM) phospholipid and fatty acid content; CM order; envelope surface charge; cell wall thickness; and mprF single nucleotide polymorphisms (SNPs) and expression profiles.
  
  
  RESULTS
  In comparison with the parental strain, both DAP-exposed and DAP-naive strains exhibited: (i) significantly reduced susceptibility to each HDP (P<0.05); (ii) thicker cell walls (P<0.05); (iii) increased synthesis of CM lysyl-phosphatidylglycerol (L-PG); (iv) reduced content of CM phosphatidylglycerol (PG); and (v) SNPs within the mprF locus No significant differences were observed between parental or variant strains in outer CM content of L-PG, CM fluidity, CM fatty acid contents, surface charge, mprF expression profiles or MprF protein content. An isolate which underwent identical in vivo passage, but without evolving increased DAP MICs, retained parental phenotypes and genotype.
  
  
  CONCLUSIONS
  THESE RESULTS SUGGEST: i) DAP MIC increases may occur in the absence of DAP exposures in vivo and may be triggered by organism exposure to endogenous HDPs: and ii) gain-in-function SNPs in mprF may contribute to such HDP-DAP cross-resistance phenotypes, although the mechanism of this relationship remains to be defined.
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles Medical Center, Torrance, California, United States of America ; David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California, United State of America.
authors.forename: Nagendra N
authors.initials: NN
authors.lastname: Mishra
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Yang
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Claudette
authors.initials: C
authors.lastname: Muller
authors.forename: Azzam
authors.initials: A
authors.lastname: Saleh-Mghir
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kuhn
authors.forename: Andreas
authors.initials: A
authors.lastname: Peschel
authors.forename: Michael R
authors.initials: MR
authors.lastname: Yeaman
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Nast
authors.forename: Barry N
authors.initials: BN
authors.lastname: Kreiswirth
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Crémieux
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Bayer
mesh_terms: D019881:Aminoacyltransferases / Q000235:genetics*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics*; D002473:Cell Wall / Q000378:metabolism; D017576:Daptomycin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D005227:Fatty Acids / Q000737:chemistry; D015964:Gene Expression Regulation, Bacterial; D005838:Genotype; D054884:Host-Pathogen Interactions; D007595:Joint Prosthesis / Q000382:microbiology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D010743:Phospholipids / Q000737:chemistry; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D005227:Fatty Acids; D010743:Phospholipids; D019881:Aminoacyltransferases; C429146:mprF protein, Staphylococcus aureus; D017576:Daptomycin