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Bacteria carrying\n mcr<\/jats:italic>\n variants do not always have colistin minimum inhibitory concentrations (MICs) above the clinical breakpoint, and there is a gap in understanding how\n mcr<\/jats:italic>\n -carrying bacteria adapt to colistin selective pressure. To address this gap, we propagated\n Escherichia coli<\/jats:italic>\n strains carrying\n mcr-3<\/jats:italic>\n or\n mcr-9<\/jats:italic>\n , which have been reported to confer different levels of colistin resistance and fitness costs, and a control strain lacking an\n mcr<\/jats:italic>\n gene in the presence of increasing concentrations of colistin. While the\n mcr-9<\/jats:italic>\n and control strains maintained their baseline colistin MICs, the colistin MIC of the strain expressing\n mcr-3<\/jats:italic>\n increased, alongside acquisition of nonsynonymous mutations in genes involved in lipopolysaccharide biosynthesis and modification. Analysis of individual\n mcr-3<\/jats:italic>\n strains that evolved during the experiment revealed that mutants exhibited improved competitive performance under colistin selection, but showed reduced fitness in standard media, or in the presence of human serum. Nonsynonymous\n lpxC<\/jats:italic>\n and\n hns<\/jats:italic>\n mutations were significant predictors of overall fitness and bacterial growth, but were infrequent among wild-type\n E. coli<\/jats:italic>\n isolates, and even less frequent in\n mcr-<\/jats:italic>\n positive wild-type\n E. coli<\/jats:italic>\n . Our results suggest that\n mcr<\/jats:italic>\n -expressing\n E. coli<\/jats:italic>\n can evolve to show increased colistin MICs; however, fitness costs may prevent these mutations from being established in natural populations. Moreover,\n E. coli<\/jats:italic>\n might control\n mcr-3<\/jats:italic>\n expression through the nucleoid protein H-NS, providing novel insights into bacterial regulation of\n mcr<\/jats:italic>\n expression.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1128\/aac.00457-26","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T15:05:24Z","timestamp":1781795124000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Acquired mutations in transcriptional regulator\n hns<\/i>\n and lipopolysaccharide biosynthesis and modification genes impact colistin resistance and fitness of\n mcr<\/i>\n -carrying\n E. coli<\/i>"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3627-9966","authenticated-orcid":true,"given":"Anna","family":"Schumann","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05bnh6r87","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Food Science, Cornell University","place":["Ithaca, USA"]},{"id":[{"id":"https:\/\/ror.org\/05bnh6r87","id-type":"ROR","asserted-by":"publisher"}],"name":"Graduate Field of Biomedical and Biological Sciences, Cornell University","place":["Ithaca, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1151-3242","authenticated-orcid":false,"given":"Ian P.","family":"O\u2019Keefe","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis, School of Dentistry, University of Maryland","place":["Baltimore, 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