Macrophage-Produced Peroxynitrite Induces Antibiotic Tolerance and Supersedes Intrinsic Mechanisms of Persister Formation

Staphylococcus aureus is a leading human pathogen that frequently causes chronic and relapsing infections. Antibiotic-tolerant persister cells contribute to frequent antibiotic failure in patients. Macrophages represent an important niche during S. aureus bacteremia, and recent work has identified a role for oxidative burst in the formation of antibiotic-tolerant S. aureus. We find that host-derived peroxynitrite, the reaction product of superoxide and nitric oxide, is the main mediator of antibiotic tolerance in macrophages. Using a collection of S. aureus clinical isolates, we find that, despite significant variation in persister formation in pure culture, all strains were similarly enriched for antibiotic tolerance following internalization by activated macrophages. Our findings suggest that host interaction strongly induces antibiotic tolerance and may negate bacterial mechanisms of persister formation established in pure culture. These findings emphasize the importance of studying antibiotic tolerance in the context of bacterial interaction with the host and suggest that modulation of the host response may represent a viable therapeutic strategy to sensitize S. aureus to antibiotics.

Automated summary

Staphylococcus aureus is a common human pathogen that often leads to chronic infections, with persister cells contributing to the failure of antibiotic treatment; host-derived peroxynitrite is identified as a major mediator of antibiotic tolerance in macrophages infected by S. aureus; these findings highlight the significant impact of host-bacterial interactions on antibiotic tolerance and suggest that modulating the host response could be a potential therapeutic strategy to enhance S. aureus sensitivity to antibiotics.