Restriction of arginine induces antibiotic tolerance in Staphylococcus aureus

• Published in: Nature communications 2024-08, Vol.15 (1), p.6734-16, Article 6734
• Main Authors: Freiberg, Jeffrey A., Reyes Ruiz, Valeria M., Gimza, Brittney D., Murdoch, Caitlin C., Green, Erin R., Curry, Jacob M., Cassat, James E., Skaar, Eric P.
• Format: Article
• Language: English
• Subjects: 45/47; 45/70; 49/23; 631/326/1320; 631/326/22/1290; 631/326/46; 64/60; 692/420/254; 82/80; Animal models; Animals; Anti-Bacterial Agents - pharmacology; Antibiotic tolerance; Antibiotics; Arginine; Arginine - metabolism; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biofilms; Biofilms - drug effects; Biofilms - growth & development; Drug Resistance, Bacterial - drug effects; Drug Resistance, Bacterial - genetics; Female; Humanities and Social Sciences; Hydrolases - genetics; Hydrolases - metabolism; Hypotheses; Impact tolerances; Inactivation; Metabolism; Mice; Microbial Sensitivity Tests; multidisciplinary; Protein biosynthesis; Protein synthesis; Protein turnover; Proteomics; Science; Science (multidisciplinary); Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - genetics; Staphylococcus aureus - metabolism; Staphylococcus infections; Transposons; Vancomycin; Vancomycin - pharmacology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51144-9

Staphylococcus aureus is responsible for a substantial number of invasive infections globally each year. These infections are problematic because they are frequently recalcitrant to antibiotic treatment. Antibiotic tolerance, the ability of bacteria to persist despite normally lethal doses of antibiotics, contributes to antibiotic treatment failure in S. aureus infections. To understand how antibiotic tolerance is induced, S. aureus biofilms exposed to multiple anti-staphylococcal antibiotics are examined using both quantitative proteomics and transposon sequencing. These screens indicate that arginine metabolism is involved in antibiotic tolerance within a biofilm and support the hypothesis that depletion of arginine within S. aureus communities can induce antibiotic tolerance. Consistent with this hypothesis, inactivation of argH , the final gene in the arginine synthesis pathway, induces antibiotic tolerance. Arginine restriction induces antibiotic tolerance via inhibition of protein synthesis. In murine skin and bone infection models, an argH mutant has enhanced ability to survive antibiotic treatment with vancomycin, highlighting the relationship between arginine metabolism and antibiotic tolerance during S. aureus infection. Uncovering this link between arginine metabolism and antibiotic tolerance has the potential to open new therapeutic avenues targeting previously recalcitrant S. aureus infections. Utilising proteomic and transposon sequencing screens, Freiberg et al. identified arginine metabolism enzymes that impact tolerance to antibiotics in Staphylococcus aureus , including in animal models of skin and bone infections.