Staphylococcus aureus
bacteremia cases are complicated by bacterial persistence and treatment failure despite the confirmed in vitro susceptibility of the infecting strain to administered
antibiotics. A high incidence of methicillin-resistant S. aureus (MRSA)
bacteremia cases are classified as persistent and are associated with poorer patient outcomes. It is still unclear how S. aureus evades the host immune system and resists
antibiotic treatment for the prolonged duration of a
persistent infection. In this study, the genetic changes and associated phenotypic traits specific to S. aureus persistent
bacteremia were identified by comparing temporally dispersed isolates from
persistent infections (persistent isolates) originating from two independent persistent S. aureus
bacteremia cases with the initial
infection isolates and with three resolved S. aureus
bacteremia isolates from the same genetic background. Several novel traits were associated specifically with both independent sets of persistent S. aureus isolates compared to both the initial isolates and the isolates from resolved
infections (resolved isolates). These traits included (i) increased growth under nutrient-poor conditions; (ii) increased tolerance of
iron toxicity; (iii) higher expression of
cell surface proteins involved in immune evasion and stress responses; and (iv) attenuated virulence in a Galleria mellonella larva
infection model that was not associated with small-colony variation or metabolic dormancy such as had been seen previously. Whole-genome sequence analysis identified different single
nucleotide mutations within the mprF genes of all the isolates with the adaptive persistence traits from both independent cases. Overall, our data indicate a novel role for MprF function during development of S. aureus persistence by increasing bacterial fitness and immune evasion.