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Adv."],"published-print":{"date-parts":[[2026,9,4]]},"abstract":"<jats:p>\n                    The mechanism by which phenotypic heterogeneity is generated within a bacterial population and leads to colistin heteroresistance has been unclear. Heteroresistance is a form of antibiotic resistance in which a minor subpopulation of resistant cells coexists with a majority susceptible population. Colistin heteroresistance is common among\n                    <jats:italic toggle=\"yes\">Enterobacter<\/jats:italic>\n                    isolates, threatens its utility as a therapeutic, and has become a model to study the fundamental bases of heteroresistance. Here, we identify the sigma factor \u03c3\n                    <jats:sup>E<\/jats:sup>\n                    as the source of heterogeneity in colistin resistance. Single-cell tracking revealed that \u03c3\n                    <jats:sup>E<\/jats:sup>\n                    is active in 1% of the population, and only those cells survive colistin exposure. However, \u03c3\n                    <jats:sup>E<\/jats:sup>\n                    expression and heterogeneity were insufficient for survival, as a mutant lacking the PhoPQ system controlling lipid A modifications necessary for colistin resistance retained heterogeneity but lost resistance. These findings lead to a paradigm in heteroresistance; the combinatorial action of regulatory systems, encompassing a heterogeneity generator and a distinct resistance generator, gives rise to colistin heteroresistance.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aec7052","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:59:26Z","timestamp":1788371966000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Combinatorial action of regulatory systems generates colistin heteroresistance"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3077-0730","authenticated-orcid":true,"given":"Jacob E.","family":"Choby","sequence":"first","affiliation":[{"name":"Emory Antibiotic Resistance Center, Atlanta, GA 30322, USA."},{"name":"Emory Vaccine Center, Atlanta, GA 30322, USA."},{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily K.","family":"Crispell","sequence":"additional","affiliation":[{"name":"Emory Antibiotic Resistance Center, Atlanta, GA 30322, USA."},{"name":"Emory Vaccine Center, Atlanta, GA 30322, USA."},{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1369-2689","authenticated-orcid":true,"given":"Muqing","family":"Ma","sequence":"additional","affiliation":[{"name":"Emory Antibiotic Resistance Center, Atlanta, GA 30322, USA."},{"name":"Department of Physics, Emory University, Atlanta, GA 30322, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8004-3175","authenticated-orcid":true,"given":"Linda M.","family":"Vu","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis, University of Maryland-Baltimore, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7551-9616","authenticated-orcid":true,"given":"Mary-Kate","family":"Key","sequence":"additional","affiliation":[{"name":"Emory Antibiotic Resistance Center, Atlanta, GA 30322, USA."},{"name":"Emory Vaccine Center, Atlanta, GA 30322, USA."},{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5016-8694","authenticated-orcid":true,"given":"Robert K.","family":"Ernst","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis, University of Maryland-Baltimore, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1594-4971","authenticated-orcid":true,"given":"Minsu","family":"Kim","sequence":"additional","affiliation":[{"name":"Emory Antibiotic Resistance Center, Atlanta, GA 30322, USA."},{"name":"Department of Physics, Emory University, Atlanta, GA 30322, USA."},{"name":"Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0980-7866","authenticated-orcid":true,"given":"David S.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Emory Antibiotic Resistance Center, Atlanta, GA 30322, USA."},{"name":"Emory Vaccine Center, Atlanta, GA 30322, USA."},{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(21)00194-8"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/jacamr\/dlae146"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanmic.2024.101010"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","unstructured":"C. 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Weiss Metabolic heterogeneity coupled with a resistance gene generates antibiotic heteroresistance. bioRxiv 641639 [Preprint] (2025). https:\/\/doi.org\/10.1101\/2025.03.11.641639.","DOI":"10.1101\/2025.03.11.641639"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aec7052","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T18:01:59Z","timestamp":1788372119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aec7052"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":64,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2026,9,4]]}},"alternative-id":["10.1126\/sciadv.aec7052"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aec7052","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]},"assertion":[{"value":"2025-10-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaec7052"}}