{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:26:28Z","timestamp":1790267188758,"version":"4.1.0"},"reference-count":23,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T00:00:00Z","timestamp":1672704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"IAME","award":["DEQ20161136698"],"award-info":[{"award-number":["DEQ20161136698"]}]},{"name":"Fondation pour la Recherche M\u00e9dicale","award":["DEQ20161136698"],"award-info":[{"award-number":["DEQ20161136698"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Colistin is a drug of last resort to treat extreme drug-resistant Enterobacterales, but is limited by dose-dependent toxicity and the emergence of resistance. A recently developed antimicrobial pseudopeptide, Pep16, which acts on the cell membrane, may be synergistic with colistin and limit the emergence of resistance. We investigated Pep16 activity against Escherichia coli with varying susceptibility to colistin, in vitro and in a murine peritonitis model. Two isogenic derivatives of E. coli CFT073 (susceptible and resistant to colistin) and 2 clinical isolates (susceptible (B119) and resistant to colistin (Af31)) were used. Pep16 activity, alone and in combination with colistin, was determined in vitro (checkerboard experiments, time\u2013kill curves, and flow cytometry to investigate membrane permeability). Toxicity and pharmacokinetic analyses of subcutaneous Pep16 were performed in mice, followed by the investigation of 10 mg\/kg Pep16 + 10 mg\/kg colistin (mimicking human concentrations) in a murine peritonitis model. Pep16 alone was inactive (MICs = 32\u201364 mg\/L; no bactericidal effect). A concentration-dependent bactericidal synergy of Pep16 with colistin was evidenced on all strains, confirmed by flow cytometry. In vivo, Pep16 alone was ineffective. When Pep16 and colistin were combined, a significant decrease in bacterial counts in the spleen was evidenced, and the combination prevented the emergence of colistin-resistant mutants, compared to colistin alone. Pep16 synergizes with colistin in vitro, and the combination is more effective than colistin alone in a murine peritonitis by reducing bacterial counts and the emergence of resistance. Pep16 may optimize colistin use, by decreasing the doses needed, while limiting the emergence of colistin-resistant mutants.<\/jats:p>","DOI":"10.3390\/antibiotics12010081","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T04:08:07Z","timestamp":1672805287000},"page":"81","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Synergistic Activity of Pep16, a Promising New Antibacterial Pseudopeptide against Multidrug-Resistant Organisms, in Combination with Colistin against Multidrug-Resistant Escherichia coli, In Vitro and in a Murine Peritonitis Model"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4937-2310","authenticated-orcid":false,"given":"Samuel","family":"Chosidow","sequence":"first","affiliation":[{"name":"IAME UMR-1137, INSERM, Universit\u00e9 de Paris, F-75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Fantin","sequence":"additional","affiliation":[{"name":"IAME UMR-1137, INSERM, Universit\u00e9 de Paris, F-75018 Paris, France"},{"name":"Service de M\u00e9decine Interne, H\u00f4pital Beaujon, AP-HP, F-92210 Clichy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5465-3969","authenticated-orcid":false,"given":"Ir\u00e8ne","family":"Nicolas","sequence":"additional","affiliation":[{"name":"SAS. Olgram, F-56580 Br\u00e9han, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Baptiste","family":"Mascary","sequence":"additional","affiliation":[{"name":"SAS. Olgram, F-56580 Br\u00e9han, France"},{"name":"Unit\u00e9 Inserm U1230 BRM, Universit\u00e9 de Rennes 1, F-35043 Rennes, France"},{"name":"Laboratoire de Pharmacologie Biologique, CHU Pontchaillou, F-35033 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Chau","sequence":"additional","affiliation":[{"name":"IAME UMR-1137, INSERM, Universit\u00e9 de Paris, F-75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Bordeau","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Inserm U1230 BRM, Universit\u00e9 de Rennes 1, F-35043 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Clemence","family":"Verdier","sequence":"additional","affiliation":[{"name":"Laboratoire de Pharmacologie Biologique, CHU Pontchaillou, F-35033 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Rocheteau","sequence":"additional","affiliation":[{"name":"SAS. Olgram, F-56580 Br\u00e9han, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6821-3131","authenticated-orcid":false,"given":"Francois","family":"Gu\u00e9rin","sequence":"additional","affiliation":[{"name":"Service de Bact\u00e9riologie-Hygi\u00e8ne Hospitali\u00e8re & CNR de la R\u00e9sistance aux Antibiotiques (Laboratoire Associ\u00e9 \u201cEnt\u00e9rocoques\u201d), CHU Pontchaillou, F-35033 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4026-9912","authenticated-orcid":false,"given":"Vincent","family":"Cattoir","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Inserm U1230 BRM, Universit\u00e9 de Rennes 1, F-35043 Rennes, France"},{"name":"Service de Bact\u00e9riologie-Hygi\u00e8ne Hospitali\u00e8re & CNR de la R\u00e9sistance aux Antibiotiques (Laboratoire Associ\u00e9 \u201cEnt\u00e9rocoques\u201d), CHU Pontchaillou, F-35033 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoire","family":"de Lastours","sequence":"additional","affiliation":[{"name":"IAME UMR-1137, INSERM, Universit\u00e9 de Paris, F-75018 Paris, France"},{"name":"Service de M\u00e9decine Interne, H\u00f4pital Beaujon, AP-HP, F-92210 Clichy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e51","DOI":"10.1016\/S1473-3099(20)30003-7","article-title":"The Lancet Infectious Diseases Commission on Antimicrobial Resistance: 6 Years Later","volume":"20","author":"Laxminarayan","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S1473-3099(11)70056-1","article-title":"Metallo-\u03b2-Lactamases: A Last Frontier for \u03b2-Lactams?","volume":"11","author":"Cornaglia","year":"2011","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","first-page":"1563.e5","article-title":"The Inoculum Effect of Escherichia coli Expressing Mcr-1 or Not on Colistin Activity in a Murine Model of Peritonitis","volume":"25","author":"Fantin","year":"2019","journal-title":"Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1128\/CMR.00064-16","article-title":"Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes","volume":"30","author":"Poirel","year":"2017","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1007\/s40262-017-0561-1","article-title":"Clinical Pharmacokinetics and Pharmacodynamics of Colistin","volume":"56","author":"Marchand","year":"2017","journal-title":"Clin. Pharmacokinet."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Abdelaziz, S.M., Aboshanab, K.M., Yahia, I.S., Yassien, M.A., and Hassouna, N.A. (2021). Correlation between the Antibiotic Resistance Genes and Susceptibility to Antibiotics among the Carbapenem-Resistant Gram-Negative Pathogens. Antibiotics, 10.","DOI":"10.3390\/antibiotics10030255"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1089\/mdr.2016.0191","article-title":"Transferability of the Mcr-1 Colistin Resistance Gene","volume":"23","author":"Poirel","year":"2017","journal-title":"Microb. Drug Resist."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S1473-3099(15)00424-7","article-title":"Emergence of Plasmid-Mediated Colistin Resistance Mechanism MCR-1 in Animals and Human Beings in China: A Microbiological and Molecular Biological Study","volume":"16","author":"Liu","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e01932-17","DOI":"10.1128\/JCM.01932-17","article-title":"Rapid Increase in Prevalence of Carbapenem-Resistant Enterobacteriaceae (CRE) and Emergence of Colistin Resistance Gene Mcr-1 in CRE in a Hospital in Henan, China","volume":"56","author":"Li","year":"2018","journal-title":"J. Clin. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S1473-3099(17)30753-3","article-title":"Discovery, Research, and Development of New Antibiotics: The WHO Priority List of Antibiotic-Resistant Bacteria and Tuberculosis","volume":"18","author":"Tacconelli","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e00079-17","DOI":"10.1128\/CMR.00079-17","article-title":"Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae","volume":"31","author":"Machuca","year":"2018","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/S1473-3099(17)30228-1","article-title":"Effect of Appropriate Combination Therapy on Mortality of Patients with Bloodstream Infections Due to Carbapenemase-Producing Enterobacteriaceae (INCREMENT): A Retrospective Cohort Study","volume":"17","author":"Salamanca","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1093\/jac\/dkab378","article-title":"Activity of the Combination of Colistin and Fosfomycin against NDM-1-Producing Escherichia coli with Variable Levels of Susceptibility to Colistin and Fosfomycin in a Murine Model of Peritonitis","volume":"77","author":"Guerin","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Nicolas, I., Bordeau, V., Bondon, A., Baudy-Floc\u2019h, M., and Felden, B. (2019). Novel Antibiotics Effective against Gram-Positive and -Negative Multi-Resistant Bacteria with Limited Resistance. PLoS Biol., 17.","DOI":"10.1371\/journal.pbio.3000337"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3074","DOI":"10.1093\/jac\/dky283","article-title":"Activity of Fosfomycin Alone or Combined with Temocillin in Vitro and in a Murine Model of Peritonitis Due to KPC-3- or OXA-48-Producing Escherichia coli","volume":"73","author":"Berleur","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1093\/jac\/dkaa347","article-title":"Dimercaptosuccinic Acid in Combination with Carbapenems against Isogenic Strains of Escherichia coli Producing or Not Producing a Metallo-\u03b2-Lactamase in Vitro and in Murine Peritonitis","volume":"75","author":"Cheminet","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1093\/jac\/dkw066","article-title":"Activity of Temocillin in a Lethal Murine Model of Infection of Intra-Abdominal Origin Due to KPC-Producing Escherichia coli","volume":"71","author":"Alexandre","year":"2016","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1093\/infdis\/137.2.122","article-title":"A Method for Testing for Synergy with Any Number of Agents","volume":"137","author":"Berenbaum","year":"1978","journal-title":"J. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1128\/AAC.40.8.1914","article-title":"Comparison of Three Different in Vitro Methods of Detecting Synergy: Time-Kill, Checkerboard, and E Test","volume":"40","author":"White","year":"1996","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1128\/AAC.00970-10","article-title":"Flow Cytometry as a Tool to Determine the Effects of Cell Wall-Active Antibiotics on Vancomycin-Susceptible and -Resistant Enterococcus Faecalis Strains","volume":"55","author":"Chau","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1128\/AAC.02018-15","article-title":"Cefotaxime and Amoxicillin-Clavulanate Synergism against Extended-Spectrum-\u03b2-Lactamase-Producing Escherichia coli in a Murine Model of Urinary Tract Infection","volume":"60","author":"Rossi","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s13756-018-0375-4","article-title":"Collateral Damage of Using Colistin in Hospitalized Patients on Emergence of Colistin-Resistant Escherichia coli and Klebsiella Pneumoniae Colonization and Infection","volume":"7","author":"Wangchinda","year":"2018","journal-title":"Antimicrob. Resist. Infect. Control"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.3389\/fmicb.2019.01160","article-title":"Sub-Inhibitory Effects of Antimicrobial Peptides","volume":"10","author":"Vasilchenko","year":"2019","journal-title":"Front. Microbiol."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/1\/81\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T17:57:01Z","timestamp":1760119021000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/1\/81"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,3]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["antibiotics12010081"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics12010081","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,3]]}}}