{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:57:02Z","timestamp":1782280622937,"version":"3.54.5"},"posted":{"date-parts":[[2023,3,21]]},"group-title":"Microbiology","reference-count":56,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,3,21]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Colistin (COL) is a cationic cyclic peptide that disrupts negatively-charged bacterial cell membranes and frequently serves as an antibiotic of last resort to combat multidrug-resistant Gram-negative bacterial infections. Emergence of the horizontally transferable plasmid-borne mobilized colistin resistance (\n                  <jats:italic>mcr<\/jats:italic>\n                  ) determinant and its spread to Gram-negative strains harboring extended-spectrum \u03b2-lactamase and carbapenemase resistance genes threatens futility of our chemotherapeutic arsenal. COL is widely regarded to have zero activity against\n                  <jats:italic>mcr+<\/jats:italic>\n                  patients based on standard antimicrobial susceptibility testing (AST) performed in enriched bacteriological growth media; consequently, the drug is withheld from patients with\n                  <jats:italic>mcr+<\/jats:italic>\n                  infections. However, these standard testing media poorly mimic in vivo physiology and omit host immune factors. Here we report previously unrecognized bactericidal activities of COL against\n                  <jats:italic>mcr-1+<\/jats:italic>\n                  isolates of\n                  <jats:italic>Escherichia coli<\/jats:italic>\n                  (EC),\n                  <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                  (KP), and\n                  <jats:italic>Salmonella enterica<\/jats:italic>\n                  (SE) in standard tissue culture media containing the physiological buffer bicarbonate. Moreover, COL promoted serum complement deposition on the\n                  <jats:italic>mcr-1+<\/jats:italic>\n                  Gram-negative bacterial surface and synergized potently with active human serum in pathogen killing. At COL concentrations readily achievable with standard dosing, the peptide antibiotic killed\n                  <jats:italic>mcr-1+<\/jats:italic>\n                  EC, KP, and SE in freshly isolated human blood proved effective as monotherapy in a murine model of\n                  <jats:italic>mcr-1+<\/jats:italic>\n                  EC bacteremia. Our results suggest that COL, currently ignored as a treatment option based on traditional AST, may in fact benefit patients with\n                  <jats:italic>mcr-1+<\/jats:italic>\n                  Gram negative infections based on evaluations performed in a more physiologic context. These concepts warrant careful consideration in the clinical microbiology laboratory and for future clinical investigation of their merits in high risk patients with limited therapeutic options.\n                <\/jats:p>","DOI":"10.1101\/2023.03.21.533661","type":"posted-content","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T23:10:14Z","timestamp":1679440214000},"source":"Crossref","is-referenced-by-count":0,"title":["Unrecognized Potent Activities of Colistin Against Clinically Important\n                  <i>mcr<\/i>\n                  + Enterobacteriaceae Revealed in Synergy with Host Immunity"],"prefix":"10.64898","author":[{"given":"Monika","family":"Kumaraswamy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"Riestra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anabel","family":"Flores","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Uchiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira","family":"Dahesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Bonds\u00e4ter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideya","family":"Seo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Sakoulas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3847-0422","authenticated-orcid":false,"given":"Victor","family":"Nizet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023032412051506000_2023.03.21.533661v1.1","doi-asserted-by":"publisher","DOI":"10.1086\/429323"},{"key":"2023032412051506000_2023.03.21.533661v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)68241-X"},{"key":"2023032412051506000_2023.03.21.533661v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(06)70580-1"},{"key":"2023032412051506000_2023.03.21.533661v1.4","doi-asserted-by":"publisher","DOI":"10.1086\/599374"},{"key":"2023032412051506000_2023.03.21.533661v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(16)00006-2"},{"key":"2023032412051506000_2023.03.21.533661v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(16)00056-6"},{"key":"2023032412051506000_2023.03.21.533661v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(16)00057-8"},{"key":"2023032412051506000_2023.03.21.533661v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(16)00009-8"},{"key":"2023032412051506000_2023.03.21.533661v1.9","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00064-16"},{"key":"2023032412051506000_2023.03.21.533661v1.10","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2014.00643"},{"key":"2023032412051506000_2023.03.21.533661v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00424-7"},{"key":"2023032412051506000_2023.03.21.533661v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03205-z"},{"key":"2023032412051506000_2023.03.21.533661v1.13","doi-asserted-by":"crossref","first-page":"941358","DOI":"10.3389\/fcimb.2022.941358","article-title":"Global epidemiology, genetic environment, risk factors and therapeutic prospects of mcr genes: A current and emerging update","volume":"12","year":"2022","journal-title":"Front. 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