Convergent Evolution of Antibiotic Tolerance in Patients with Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia

Abstract

Severe infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are often complicated by persistent bacteremia (PB) despite active antibiotic therapy. Antibiotic resistance rarely contributes to MRSA-PB, suggesting an important role for antibiotic tolerance pathways.

Staphylococcus aureus host interactions and adaptation

“…Building on the recognition that adaptive evolution drives important clinical outcomes in S. aureus infections including both invasiveness of colonizing strains 137 , and persistence and treatment failure in invasive strains 130 , 143 , approaches to detect mutation in high-risk adaptive genes could support clinical decision making. This strategy has been successfully used in cancer medicine, whereby genomics approaches are used to detect driver mutations 169 .…”

“…Besides agr , there are other key core genes targeted by adaptive evolution that have regulatory functions: these include the essential cell-wall regulatory system walKR 24 , rsp (transcription factor repressor of surface proteins) 136 , 139 and the adaptor protein yjbH 130 , 140 , that interacts with the transcriptional regulator encoded by spx 141 . Recently, within-host genomic studies have also indicated that metabolic genes such as sucA - sucB are hotspots of bacterial host adaptation 130 , 142 , 143 . These adaptive processes seem to be specific to colonization and infection.…”

“…Although these adaptations often lead to reduced mortality in animal models, secondary mutations in adapted low-toxicity strains can restore virulence 138 , which highlights the complexity of toxicity trade-offs during infection. Finally, metabolic adaptation has been recently documented in persistent bacteraemia with convergent mutation in citrate metabolism genes associated with metabolic antibiotic resistance 143 .…”

Antibiotic tolerance and persistence have distinct fitness trade-offs

“…Our results so far suggest that because of its high penetrance antibiotic tolerance, is a much more effective means of drug survival than antibiotic persistence, which only allows the survival of a few bacteria. However, the flip side of tolerance is that it imposes a restricted growth rate to all cells in the population, which might explain why tolerance mutations were not commonly selected for following cyclical antibiotic exposure of several different bacterial pathogens [12,[26][27][28][29][30][31]. One hypothesis is that the fitness cost of tolerance mutations is too high in the absence of antibiotic treatment to be selected for over time.…”

“…In clinical settings, periodic rounds of antimicrobial therapy have been often associated with the appearance of hyper-persistence [26][27][28][29][30][31]. Interestingly, a hipA7 variant, the E. coli phenotypic equivalent of Salmonella shpAB1, was identified in patients with recurrent UTIs [31,36].…”