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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.

plos one

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