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After ceftriaxone replaced chloramphenicol (CHL) as empiric therapy for suspected sepsis in Malawi in 2004, extended-spectrum beta-lactamase (ESBL)-E rapidly emerged. Concurrently, resistance to CHL in\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    and\n                    <jats:italic>Klebsiella<\/jats:italic>\n                    spp. decreased, raising the possibility of CHL re-introduction. However, many phenotypically susceptible isolates still carry CHL acetyltransferase (\n                    <jats:italic>cat<\/jats:italic>\n                    ) genes. To understand the molecular mechanisms and stability of this re-emerging CHL susceptibility we use a combination of genomics, phenotypic susceptibility assays, experimental evolution, and functional assays for CAT activity. Here, we show that of 840 Malawian\n                    <jats:italic>E. coli<\/jats:italic>\n                    and\n                    <jats:italic>Klebsiella<\/jats:italic>\n                    spp. isolates, 31% have discordant CHL susceptibility genotype\u2013phenotype, and we select a subset of 42 isolates for in-depth analysis. Stable degradation of\n                    <jats:italic>cat<\/jats:italic>\n                    genes by insertion sequences leads to re-emergence of CHL susceptibility. Our study suggests that CHL could be reintroduced as a reserve agent for critically ill patients with ESBL-E infections in Malawi and similar settings and highlights the ongoing challenges in inferring antimicrobial resistance from sequence data.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-53391-2","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T11:03:06Z","timestamp":1729249386000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase-producing Enterobacterales"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1132-5348","authenticated-orcid":false,"given":"Fabrice E.","family":"Graf","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0578-789X","authenticated-orcid":false,"given":"Richard N.","family":"Goodman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Gallichan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally","family":"Forrest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1189-4751","authenticated-orcid":false,"given":"Esther","family":"Picton-Barlow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice J.","family":"Fraser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3426-1044","authenticated-orcid":false,"given":"Minh-Duy","family":"Phan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalitso","family":"Mphasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6668-9179","authenticated-orcid":false,"given":"Alasdair T. 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