Abstract
BackgroundPrevious 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).MethodsIn 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.ResultsIn 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.ConclusionsThese 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.
Highlights
S. aureus is a prominent human pathogen which can cause severe infections including endocarditis, septicemia, and osteomyelitis [1,2,3]
This observation suggested that endogenous host factors interacting with the microorganism during the course of infection could promote the DAP-R phenotype
Four methicillin-resistant Staphylococcus aureus (MRSA) strains were primarily used in this study, including: i) a parental DAP-S strain used to induce prosthetic joint infection in rabbits (L-271); and ii) three strains with increased DAP minimal inhibitory concentrations (MICs) isolated from either DAP-treated or DAP-untreated rabbits (L-8 and L56; and L-16, respectively) [5]
Summary
S. aureus is a prominent human pathogen which can cause severe infections including endocarditis, septicemia, and osteomyelitis [1,2,3]. 17 17 17 30 rabbit MRSA prothetic joint infection model [5], which closely parallels similar post-operative infections in human [6]. Spontaneous emergence of MRSA with decreased susceptibility to DAP was detected in 2/9 untreated control animals with joint infection. This observation suggested that endogenous host factors interacting with the microorganism during the course of infection could promote the DAP-R phenotype. 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)
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