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Here we report that loss of the global regulatory protein cyclic AMP (cAMP) receptor protein (CRP) or its allosteric effector, cAMP, reduces susceptibility to fluoroquinolones. A \u0394\n            <jats:italic>crp<\/jats:italic>\n            mutation was synergistic with the primary fluoroquinolone resistance allele\n            <jats:italic>gyrA83<\/jats:italic>\n            , thus able to contribute to clinically relevant resistance. Decreased susceptibility to fluoroquinolones could be partly explained by decreased expression of the outer membrane porin genes\n            <jats:italic>ompA<\/jats:italic>\n            and\n            <jats:italic>ompF<\/jats:italic>\n            with a concomitant increase in the expression of the ciprofloxacin resistance efflux pump gene\n            <jats:italic>acrB<\/jats:italic>\n            in \u0394\n            <jats:italic>crp<\/jats:italic>\n            cells. Expression of\n            <jats:italic>gyrAB<\/jats:italic>\n            , which encode the DNA supercoiling enzyme GyrAB, which is blocked by fluoroquinolones, and expression of\n            <jats:italic>topA<\/jats:italic>\n            , which encodes the dominant supercoiling-relaxing enzyme topoisomerase I, were unchanged in \u0394\n            <jats:italic>crp<\/jats:italic>\n            cells. Yet \u0394\n            <jats:italic>crp<\/jats:italic>\n            cells maintained a more relaxed state of DNA supercoiling, correlating with an observed increase in topoisomerase IV (\n            <jats:italic>parCE<\/jats:italic>\n            ) expression. Surprisingly, the \u0394\n            <jats:italic>crp<\/jats:italic>\n            mutation had the unanticipated effect of enhancing fitness in the presence of fluoroquinolone antibiotics, which can be explained by the observation that exposure of \u0394\n            <jats:italic>crp<\/jats:italic>\n            cells to ciprofloxacin had the counterintuitive effect of restoring wild-type levels of DNA supercoiling. Consistent with this, \u0394\n            <jats:italic>crp<\/jats:italic>\n            cells did not become elongated or induce the SOS response when challenged with ciprofloxacin. These findings implicate the combined action of multiple drug resistance mechanisms in \u0394\n            <jats:italic>crp<\/jats:italic>\n            cells: reduced permeability and elevated efflux of fluoroquinolones coupled with a relaxed DNA supercoiling state that buffers cells against GyrAB inhibition by fluoroquinolones.\n          <\/jats:p>","DOI":"10.1128\/aac.01666-17","type":"journal-article","created":{"date-parts":[[2017,9,6]],"date-time":"2017-09-06T00:30:20Z","timestamp":1504657820000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":23,"title":["The Global Regulatory Cyclic AMP Receptor Protein (CRP) Controls Multifactorial Fluoroquinolone Susceptibility in Salmonella enterica Serovar Typhimurium"],"prefix":"10.1128","volume":"61","author":[{"given":"Stefani C.","family":"Kary","sequence":"first","affiliation":[{"name":"Department of Biology, University of Regina, Regina, Saskatchewan, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua R. K.","family":"Yoneda","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Regina, Regina, Saskatchewan, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen C.","family":"Olshefsky","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Regina, Regina, Saskatchewan, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Regina, Regina, Saskatchewan, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven B.","family":"West","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Regina, Regina, Saskatchewan, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1560-8572","authenticated-orcid":false,"given":"Andrew D. 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