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Paradoxically,\n            <jats:italic>agr<\/jats:italic>\n            -defective mutants are frequently recovered from patients, especially those persistently infected with\n            <jats:italic>S.\u00a0aureus<\/jats:italic>\n            . We found that an\n            <jats:italic>agr<\/jats:italic>\n            deficiency increased survival of cultured bacteria during severe stress, such as treatment with gentamicin, ciprofloxacin, heat, or low pH. With daptomycin, deletion of\n            <jats:italic>agr<\/jats:italic>\n            decreased survival. Therefore,\n            <jats:italic>agr<\/jats:italic>\n            activity can be either detrimental or protective, depending on the type of lethal stress. Deletion of\n            <jats:italic>agr<\/jats:italic>\n            had no effect on the ability of the antimicrobials to block bacterial growth, indicating that\n            <jats:italic>agr<\/jats:italic>\n            effects are limited to lethal action. Thus, the effect of an\n            <jats:italic>agr<\/jats:italic>\n            deletion is on bacterial tolerance, not resistance. For gentamicin and daptomycin, activity can be altered by\n            <jats:italic>agr<\/jats:italic>\n            -regulated secreted factors. For ciprofloxacin, a detrimental function was downregulation of glutathione peroxidase (\n            <jats:italic>bsaA<\/jats:italic>\n            ), an enzyme responsible for defense against oxidative stress. Deficiencies in\n            <jats:italic>agr<\/jats:italic>\n            and\n            <jats:italic>bsaA<\/jats:italic>\n            were epistatic for survival, consistent with\n            <jats:italic>agr<\/jats:italic>\n            having a destructive role mediated by reactive oxygen species. Enhanced susceptibility to lethal stress by wild-type\n            <jats:italic>agr<\/jats:italic>\n            , particularly antimicrobial stress, helps explain why inactivating mutations in\n            <jats:italic>S.\u00a0aureus agr<\/jats:italic>\n            commonly occur in hospitalized patients during infection. Moreover, the\n            <jats:italic>agr<\/jats:italic>\n            quorum-sensing system of\n            <jats:italic>S.\u00a0aureus<\/jats:italic>\n            provides a clinically relevant example in which a single-step change in the response to severe stress alters the evolutionary path of a pathogen during infection.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            When phenotypes produced in response to an environmental stress are inadequate to buffer against that stress, changes that do buffer may become genetically encoded by natural selection. A clinically relevant example is seen with\n            <jats:italic>S.\u00a0aureus<\/jats:italic>\n            mutants that are deficient in the key virulence regulator\n            <jats:italic>agr<\/jats:italic>\n            . Paradoxically, defects in\n            <jats:italic>agr<\/jats:italic>\n            are selected during serious hospital infection and have been associated with worse outcome. The current work helps resolve this paradox:\n            <jats:italic>agr<\/jats:italic>\n            mutants are often less readily killed by lethal stressors without affecting MIC, a phenomenon known as tolerance. Our results indicate that tolerance, which would not be detected as resistance, can be selected in clinical settings. The data also support the ideas that (i)\n            <jats:italic>S.\u00a0aureus<\/jats:italic>\n            broadly hedges against environmental change and stress through genome plasticity, (ii) reactive oxygen can be involved in the self-destructive response in bacteria, and (iii) therapeutic targeting of\n            <jats:italic>agr<\/jats:italic>\n            and virulence can be counterproductive.\n          <\/jats:p>","DOI":"10.1128\/mbio.01476-17","type":"journal-article","created":{"date-parts":[[2017,10,25]],"date-time":"2017-10-25T00:10:24Z","timestamp":1508890224000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":18,"title":["Tuning of the Lethal Response to Multiple Stressors with a Single-Site Mutation during Clinical Infection by\n            <i>Staphylococcus aureus<\/i>"],"prefix":"10.1128","volume":"8","author":[{"given":"Krishan","family":"Kumar","sequence":"first","affiliation":[{"name":"Departments of Medicine and Microbiology, New York University School of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Drlica","sequence":"additional","affiliation":[{"name":"Public Health Research Institute and Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Shopsin","sequence":"additional","affiliation":[{"name":"Departments of Medicine and 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