{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:39:13Z","timestamp":1762868353176,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T00:00:00Z","timestamp":1606694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CAPES-Brazil (Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior)","award":["-"],"award-info":[{"award-number":["-"]}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["Vacation Scholarship 202526\/Z\/16\/Z"],"award-info":[{"award-number":["Vacation Scholarship 202526\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cationic antimicrobial peptides have attracted interest, both as antimicrobial agents and for their ability to increase cell permeability to potentiate other antibiotics. However, toxicity to mammalian cells and complexity have hindered development for clinical use. We present the design and synthesis of very short cationic peptides (3\u20139 residues) with potential dual bacterial membrane permeation and efflux pump inhibition functionality. Peptides were designed based upon in silico similarity to known active peptides and efflux pump inhibitors. A number of these peptides potentiate the activity of the antibiotic novobiocin against susceptible Escherichia coli and restore antibiotic activity against a multi-drug resistant E. coli strain, despite having minimal or no intrinsic antimicrobial activity. Molecular modelling studies, via docking studies and short molecular dynamics simulations, indicate two potential mechanisms of potentiating activity; increasing antibiotic cell permeation via complexation with novobiocin to enable self-promoted uptake, and binding the E. coli RND efflux pump. These peptides demonstrate potential for restoring the activity of hydrophobic drugs.<\/jats:p>","DOI":"10.3390\/ijms21239134","type":"journal-article","created":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T20:10:22Z","timestamp":1606767022000},"page":"9134","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synthesis and in Silico Modelling of the Potential Dual Mechanistic Activity of Small Cationic Peptides Potentiating the Antibiotic Novobiocin against Susceptible and Multi-Drug Resistant Escherichia coli"],"prefix":"10.3390","volume":"21","author":[{"given":"Ilaria","family":"Passarini","sequence":"first","affiliation":[{"name":"School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro Ernesto de","family":"Resende","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Soares","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadeh","family":"Tahmasi","sequence":"additional","affiliation":[{"name":"School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Stapleton","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Malkinson","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4848-2737","authenticated-orcid":false,"given":"Mire","family":"Zloh","sequence":"additional","affiliation":[{"name":"School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK"},{"name":"NanoPuzzle Medicines Design, Stevenage SG1 2DX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3822-0028","authenticated-orcid":false,"given":"Sharon","family":"Rossiter","sequence":"additional","affiliation":[{"name":"School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Passarini, I., Rossiter, S., Malkinson, J., and Zloh, M. 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