Abstract
Previous studies showed serial 20 d in vitro passage of MRSA strain MW2 in sublethal daptomycin (DAP) resulted in diverse perturbations in both cell membrane (CM) and cell wall (CW) characteristics, including increased CM rigidity; increased CW thickness; “gain-in-function” single nucleotide polymorphisms (SNPs) in the mprF locus (i.e., increased synthesis and translocation of lysyl-phosphatidylglycerol (L-PG)); progressive accumulation of SNPs in yyc and rpo locus genes; reduced carotenoid production; cross-resistance to innate host defense peptides. The current study was designed to characterize the reproducibility of these phenotypic and genotypic modifications following in vitro serial passages of the same parental strain. After a second 20d serial in vitro passage of parental MW2, emergence of DAP-R was associated with evolution of several phenotypes closely mirroring previous passage outcomes. However, in contrast to the initial serial passage strain set, we observed (i) only modest increase in L-PG synthesis and no increase in L-PG outer CM translocation; (ii) significantly increased carotenoid synthesis (P < 0.05); (iii) a different order of SNP accumulations (mprF ≫ rpoB ≫ yycG); (iv) a different cadre and locations of such SNPs. Thus, MRSA strains are not “pre-programmed” to phenotypically and/or genotypically adapt in an identical manner during induction of DAP resistance.
Highlights
Invasive Staphylococcus aureus infections are rapidly increasing worldwide
To expand the knowledge base about potential mechanisms of DAP-R, as well as general staphylococcal responses to cationic peptide-induced stress, we examined the reproducibility of genotypic and phenotypic adaptations to serial in vitro DAP exposures in MRSA strain, MW2
We took advantage of previously published data which had catalogued both phenotypic and genotypic modifications occurring during serial in vitro passage in DAP [5, 6] and compared those to a separate but parallel passage study using the same parental MRSA strain
Summary
Invasive Staphylococcus aureus infections are rapidly increasing worldwide. The acquisition of multiantibiotic resistances, especially amongst MRSA strains, poses a major problem for clinicians [1,2,3]. We and others have identified several genetic loci which correlate to the DAPresistant (DAP-R) phenotype, including mprF, vraRS, tag, and dltABCD [6,7,8,9]. In these scenarios, either genotypic overexpression and/or phenotypic gains-in-function of these loci were observed, usually featuring single nucleotide polymorphisms (SNPs) [2, 6, 10]. Many, but not all DAP-R S. aureus isolates exhibit a thickened cell wall (CW) phenotype [11]. These investigations have strongly suggested that the DAP-R phenotype is multifactorial and probably strainspecific
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