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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:p>\n                    <jats:italic toggle=\"yes\">Acinetobacter baumannii<\/jats:italic>\n                    is an\n                    <jats:italic toggle=\"yes\">Enterococcus<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">Staphylococcus<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">Klebsiella<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">Acinetobacter<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">Pseudomonas<\/jats:italic>\n                    , and\n                    <jats:italic toggle=\"yes\">Enterobacter<\/jats:italic>\n                    species (ESKAPE) pathogen linked to healthcare-associated diseases. Due to evolved resistance, last-resort antibiotics such as the lipooligosaccharide (LOS)-targeting colistin are increasingly used to treat multidrug-resistant isolates. To track the evolution of colistin resistance within a host, we performed sequential oropharyngeal infections in immunocompetent or immune-depleted mice in the presence of inhaled colistin. Both resistant and heteroresistant\n                    <jats:italic toggle=\"yes\">A. baumannii<\/jats:italic>\n                    strains emerged with\n                    <jats:italic toggle=\"yes\">pmrB<\/jats:italic>\n                    mutations that efficiently competed with the susceptible parent in the presence of colistin. These\n                    <jats:italic toggle=\"yes\">pmrB<\/jats:italic>\n                    mutants had a fitness cost in the absence of colistin treatment but retained their ability to colonize the host. In contrast, LOS-deficient\n                    <jats:italic toggle=\"yes\">A. baumannii<\/jats:italic>\n                    mutants removed the target of colistin, but such mutants were unable to colonize the lung. The two pathogenic\n                    <jats:italic toggle=\"yes\">pmrB<\/jats:italic>\n                    mutants showed clear evidence of LOS modification, which was linked to increased transcription of LOS modification enzymes, including the product of the cryptic\n                    <jats:italic toggle=\"yes\">eptA<\/jats:italic>\n                    gene. Spontaneous insertion mutations that caused hyperexpression of\n                    <jats:italic toggle=\"yes\">eptA<\/jats:italic>\n                    allowed the heteroresistant mutant to develop clinically significant colistin resistance. Insertion mutations upstream of the\n                    <jats:italic toggle=\"yes\">eptA<\/jats:italic>\n                    gene or those disrupting\n                    <jats:italic toggle=\"yes\">hns<\/jats:italic>\n                    , which encodes a small histone-like protein, resulted in increased\n                    <jats:italic toggle=\"yes\">eptA<\/jats:italic>\n                    transcript, linking expression of this protein to clinically significant resistance. A resistant variant derived from the heteroresistant parent was stable in the absence of drug, but continued passaging selected for colistin-resensitized pseudorevertants that were largely due to disruption of the LOS modification enzymes. Therefore, colistin heteroresistance is an early stage in the stepwise acquisition of stable colistin resistance in\n                    <jats:italic toggle=\"yes\">A. baumannii<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1073\/pnas.2515303123","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T20:00:21Z","timestamp":1767038421000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":8,"title":["Resistance, heteroresistance, and fitness costs drive colistin treatment failure during\n                    <i>Acinetobacter baumannii<\/i>\n                    pneumonia"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6106-2438","authenticated-orcid":false,"given":"Juan","family":"Hernandez-Bird","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bixi","family":"He","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah M.","family":"VanOtterloo","sequence":"additional","affiliation":[{"name":"Department of Microbiology, College of Arts and Sciences, University of Georgia","place":["Athens"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth B.","family":"Billings","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwen","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella I. C.","family":"Teodoro","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"Echlin","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital","place":["Memphis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1798-1760","authenticated-orcid":false,"given":"Jason M.","family":"Rosch","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital","place":["Memphis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6134-1800","authenticated-orcid":false,"given":"M. Stephen","family":"Trent","sequence":"additional","affiliation":[{"name":"Department of Microbiology, College of Arts and Sciences, University of Georgia","place":["Athens"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph R.","family":"Isberg","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"e_1_3_4_1_2","unstructured":"Centers for Disease Control and Prevention (U.S.) \u201cAntibiotic resistance threats in the United States 2019\u201d (Centers for Disease Control and Prevention (U.S.) 2019)."},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011520"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00058-16"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics9030119"},{"key":"e_1_3_4_5_2","unstructured":"World Health Organization WHO bacterial priority pathogens list 2024: Bacterial pathogens of public health importance to guide research development and strategies to prevent and control antimicrobial resistance (2024). https:\/\/www.who.int\/publications\/i\/item\/9789240093461."},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01110-18"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00006-08"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/432583"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2024.102315"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-16373-0_5"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00284-09"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.00435-23"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00256-11"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00515-15"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkab363"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02442-17"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00788-18"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-019-0218-1"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007726"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001346"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46571-7"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-018-0342-0"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.14240"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.13459"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00356-17"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35717-0"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1806714115"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.13872"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics6040028"},{"key":"e_1_3_4_30_2","first-page":"1","article-title":"Transition of colistin dependence into colistin resistance in Acinetobacter baumannii","volume":"7","author":"Lee J. 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