Abstract
BackgroundTolerance to antibiotics and persistence are associated with antibiotic treatment failures, chronic-relapsing infections, and emerging antibiotic resistance in various bacteria, including Staphylococcus aureus. Mechanisms of persistence are largely unknown, yet have been linked to physiology under low-ATP conditions and the metabolic-inactive state. EttA is an ATP-binding cassette protein, linked in Eschrechia coli to ribosomal hibernation and fitness in stationary growth phase, yet its role in S. aureus physiology is unknown.ResultsUsing whole genome sequencing (WGS) of serial clinical isolates, we identified an EttA-negative S. aureus mutant (ettAstop), and its isogenic wild-type counterpart. We used these two isogenic clones to investigate the role of ettA in S. aureus physiology in starvation and antibiotic stress, and test its role in persistence and antibiotic tolerance. ettAstop and its WT counterpart were similar in their antibiotic resistance profiles to multiple antibiotics. Population dynamics of ettAstop and the WT were similar in low-nutrient setting, with similar recovery from stationary growth phase or starvation. Supra-bacteriocidal concentration of cefazolin had the same killing effect on ettAstop and WT populations, with no difference in persister formation.ConclusionsLack of ettA does not affect S. aureus antibiotic resistance, beta-lactam tolerance, resilience to starvation or fitness following starvation. We conclude the role of ettA in S. aureus physiology is limited or redundant with another, unidentified gene. WGS of serial clinical isolates may enable investigation of other single genes involved in S. aureus virulence, and specifically persister cell formation.
Highlights
Tolerance to antibiotics and persistence are associated with antibiotic treatment failures, chronicrelapsing infections, and emerging antibiotic resistance in various bacteria, including Staphylococcus aureus
Isolation of an Energy-dependent translational throttle protein (EttA)-negative S. aureus mutant and its isogenic wild-type strain We used S. aureus strains isolated from serial blood cultures during a continuous S. aureus bacteremia
No other mutations were found in this clone, ettAstop, as compared to the other Wild type (WT) S. aureus clones isolated from this patient
Summary
Tolerance to antibiotics and persistence are associated with antibiotic treatment failures, chronicrelapsing infections, and emerging antibiotic resistance in various bacteria, including Staphylococcus aureus. EttA is an ATP-binding cassette protein, linked in Eschrechia coli to ribosomal hibernation and fitness in stationary growth phase, yet its role in S. aureus physiology is unknown. Considering the link between persistence in S. aureus and stationary growth phase dynamics, [5] we hypothesized that EttA in S. aureus may be involved in antibiotic tolerance, resistance to nutrient depletion, and emergence from stationary growth phase. We tested these hypotheses using an ettA-negative S. aureus clinical mutant, comparing it to its isogenic ettA wild-type strain
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