EttA is likely non-essential in Staphylococcus aureus persistence, fitness or resistance to antibiotics
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RESEARCH ARTICLE
Open Access
EttA is likely non-essential in Staphylococcus aureus persistence, fitness or resistance to antibiotics Michal Meir1*, Anna Rozenblit3, Simona Fliger3, Yuval Geffen2 and Daniel Barkan3
Abstract Background: Tolerance to antibiotics and persistence are associated with antibiotic treatment failures, chronicrelapsing 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. Results: Using 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. Conclusions: Lack 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. Keywords: Staphylococcus aureus, Antibiotic resistance, Antibiotic tolerance, Persistence, Fitness, Killing curve, Ribosomal hibernation
Background Staphylococcus aureus is a major human pathogen, responsible for a variety of acute, as well as chronic and relapsing infections such as osteomyelitis and endocarditis and is notorious for its ability to form biofilm on implanted devices. Persisters are dormant phenotypic variants of bacterial cells that are tolerant to killing by antibiotics, and are associated with chronic infections * Correspondence: [email protected] 1 The Ruth Rappaport Children’s Hospital, Rambam Health Care Campus, Haifa, Israel Full list of author information is available at the end of the article
and antibiotic treatment failures [1]. It has been recently reported that emergence of persister S. aureus bacteria in a patient receiving seemingly adequate treatment, precedes and facilitates the emergence of true resistant bacteria [2]. While mechanisms of persistence appear to be heterogeneous and mostly poorly characterized, it appears that many of them involve tra
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