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While many species have the potential to develop antibiotic resistance, understanding the barriers to resistance emergence in the clinic remains poorly understood. A prime example of this is fluroquinolone resistance in\n            <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n            , whereby, despite continued utilization, resistance to this class of antibiotic remains rare. In this study, we found that the predominant pathways for developing resistance to this antibiotic class severely compromised the infectious capacity of the pneumococcus, providing a key impediment for the emergence of resistance. Using\n            <jats:italic>in vivo<\/jats:italic>\n            models of experimental evolution, we found that\n            <jats:italic>S. pneumoniae<\/jats:italic>\n            responds to repeated fluoroquinolone exposure by modulating key metabolic pathways involved in the generation of redox molecules, which leads to antibiotic treatment failure in the absence of appreciable shifts in resistance levels. These data underscore the complex pathways available to pathogens to evade antibiotic mediating killing via antibiotic tolerance.\n          <\/jats:p>","DOI":"10.1128\/mbio.02828-23","type":"journal-article","created":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T14:00:40Z","timestamp":1704808840000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["<i>Streptococcus pneumoniae<\/i>\n            favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolones"],"prefix":"10.1128","volume":"15","author":[{"given":"Tina H.","family":"Dao","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee, 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