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We optimised the lead peptide by increasing its net positive charge, its lipophilicity through <jats:italic>N<\/jats:italic>\u2010terminal fatty acid acylation or incorporation of a Trp residue, and by synthesising head\u2010to\u2010tail cyclic peptides under <jats:italic>pseudo\u2013high\u2010dilution<\/jats:italic> conditions. All peptides were screened for antimicrobial and antifungal activity, and toxicity was determined against human red blood cells. The two most potent peptide analogues were the linear peptide <jats:bold>P6\u2010W6R8<\/jats:bold> and its head\u2010to\u2010tail cyclic analogue <jats:bold>cP6\u2010W6R8<\/jats:bold> displaying minimum inhibitory concentrations of 0.4\u20136.6\u2009\u03bcM against Gram\u2010positive and Gram\u2010negative bacteria and 6.2\u201313\u2009\u03bcM against fungi. All peptides showed low haemolytic activity except for two of the lipopeptides, in which haemolytic activity correlated with increasing acyl chain length. Mode of action studies using bacterial biosensor strains revealed a membrane disruptive effect of both the linear and the cyclic peptide. Overall, the results of our study demonstrated that relatively simple structural modifications could be successfully employed in the development of potent antimicrobial lead peptides derived from marine natural products.<\/jats:p>","DOI":"10.1002\/psc.70025","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T02:21:12Z","timestamp":1745893272000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Antimicrobial Activity of Short Analogues of the Marine Peptide EeCentrocin 1: Synthesis of Lipopeptides and Head\u2010to\u2010Tail Cyclic Peptides and Mechanism of Action Studies"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5530-5029","authenticated-orcid":false,"given":"Danijela","family":"Simonovic","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Faculty of Health Sciences UiT The Arctic University of Norway  Troms\u00f8 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