title: Impact of daptomycin resistance on Staphylococcus aureus virulence.
abstract: Daptomycin resistance (DAP(R)) in Staphylococcus aureus is associated with mutations in genes that are also implicated in staphylococcal pathogenesis. Using a laboratory-derived series of DAP exposed strains, we showed a relationship between increasing DAP MIC and reduced virulence in a Galleria mellonella infection model. Point mutations in walK and rpoC led to cumulative reductions in virulence and simultaneous increases in DAP MIC. A point mutation to mprF did not impact on S.aureus virulence; however deletion of mprF led to virulence attenuation and hyper-susceptibility to DAP. To validate our findings in G. mellonella, we confirmed the attenuated virulence of select isolates from the laboratory-derived series using a murine septicaemia model. As a corollary, we showed significant virulence reductions for clinically-derived DAP(R) isolates compared to their isogenic, DAP-susceptible progenitors (DAP(S)). Intriguingly, each clinical DAP(R) isolate was persistent in vivo. Taken together, it appears the genetic correlates underlying daptomycin resistance in S. aureus also alter pathogenicity.
authors.affiliation: a Department of Microbiology ; School of Biomedical Sciences; Monash University ; Melbourne , Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Cameron
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Mortin
authors.forename: Aileen
authors.initials: A
authors.lastname: Rubio
authors.forename: Eleftherios
authors.initials: E
authors.lastname: Mylonakis
authors.forename: Robert C
authors.initials: RC
authors.lastname: Moellering
authors.forename: George M
authors.initials: GM
authors.lastname: Eliopoulos
authors.forename: Anton Y
authors.initials: AY
authors.lastname: Peleg
mesh_terms: D019881:Aminoacyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D017576:Daptomycin / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D005838:Genotype; D007814:Larva / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D009036:Moths / Q000382:microbiology; D010641:Phenotype; D017354:Point Mutation; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D019881:Aminoacyltransferases; C429146:mprF protein, Staphylococcus aureus; D017576:Daptomycin
keywords: Galleria mellonella; S. aureus; bacterial persistence; mprF; walK
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