{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T05:17:06Z","timestamp":1787807826119,"version":"build-2784847793"},"reference-count":79,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Weill Cornell Medicine","award":["U54AG089334"],"award-info":[{"award-number":["U54AG089334"]}]},{"award":["U54AG089334"],"award-info":[{"award-number":["U54AG089334"]}],"id":[{"id":"https:\/\/ror.org\/02r109517","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background\/Objectives: Antimicrobial peptides (AMPs) are considered alternatives to classical antibiotics due to limited resistance development in bacteria. However, bacteria can develop resistance to AMPs through evolutionary adaptation, including oligosaccharide modifications and multidrug efflux pumps. Further research is needed to elucidate the defense mechanisms employed against AMPs to address the emerging resistance problem. Pexiganan is a cationic peptide with effective broad-spectrum antimicrobial activity. The aim of this study is to elucidate the genomic and transcriptomic basis of E. coli\u2019s evolutionary adaptation to pexiganan. Methods: The E. coli ATCC BAA-2523 strain became resistant to pexiganan via evolutionary adaptation methodologies. Whole-genome and transcriptome analyses of resistant and susceptible populations were conducted using Nanopore sequencing and Illumina RNA sequencing, respectively. Results: Resistance development became particularly evident after 15 \u00b5g\/mL, and the bacteria demonstrated the ability to grow even at high doses (up to 1000 \u00b5g\/mL). Increases in expression levels of classical ARGs such as emrB, acrF, OXA, sul2, and dfrA14 in the pexiganan-resistant strain indicate that bacteria have the potential for broad-spectrum resistance to other antibiotics alongside pexiganan. Missense mutations have been identified in the phosphatidylserine synthase and cardiolipin synthase genes, which are involved in membrane biosynthesis. Increased expression was observed in the membrane-bound lytic murein transglucosylase (mltF), the murein hydrolase activator (EnvC), and the Antigen 43 (Ag43) gene. Conclusions: Pexiganan may not only target the cell membrane but also trigger the bacterium\u2019s overall transcriptional response and cross-resistance and MDR systems. Upregulation of multidrug efflux pumps, lytic murein transglucosylase, the murein hydrolase activator and the Antigen 43 gene might be associated with resistance. In addition, the missense mutation was detected in the membrane biosynthesis genes pssA and clsB. In vivo infection models, targeted functional genomics, and comprehensive phenotypic cross-resistance testing will be required to validate our results.<\/jats:p>","DOI":"10.3390\/antibiotics15090825","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:04:30Z","timestamp":1787648670000},"page":"825","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adaptive Response of Escherichia coli to Pexiganan: Insights from Genomic Analysis"],"prefix":"10.3390","volume":"15","author":[{"given":"K\u00fcbra","family":"Can Kurt","sequence":"first","affiliation":[{"name":"Department of Basic Medical Sciences, Hamidiye Faculty of Dentistry, University of Health Sciences, Istanbul 34668, T\u00fcrkiye"},{"name":"Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5990-9214","authenticated-orcid":false,"given":"Liam F.","family":"Katzin","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Landon","family":"Tamaddon","sequence":"additional","affiliation":[{"name":"Columbia College, Columbia University, New York, NY 10027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8722-591X","authenticated-orcid":false,"given":"Ali","family":"Arslan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Institute of Natural Sciences, Y\u0131ld\u0131z Technical University, Istanbul 34220, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"Lucaci","sequence":"additional","affiliation":[{"name":"Department of Systems and Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1850-1642","authenticated-orcid":false,"given":"Christopher E.","family":"Mason","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA"},{"name":"Department of Systems and Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Sharma, S., Chauhan, A., Ranjan, A., Mathkor, D.M., Haque, S., Ramniwas, S., Tuli, H.S., Jindal, T., and Yadav, V. 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