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Non\u2010ribosomal peptide natural products that bind Lipid II, such as vancomycin, represent a promising source for such agents. The fungal defensin plectasin is one of a family of ribosomally produced miniproteins that also exert antimicrobial activity via Lipid II binding. Made up entirely of canonical amino acids, these molecules are potentially more susceptible to degradation by protease enzymes than non\u2010ribosomal counterparts. Here, we report the development of proteomimetic variants of plectasin through the systematic incorporation of artificial backbone connectivity in the domain. An iterative secondary\u2010structure\u2010based design scheme yields a variant with a tertiary fold indistinguishable from the prototype natural product, potent activity against Gram positive bacteria, and low mammalian cell toxicity. Backbone modification is shown to improve oxidative folding efficiency of the disulfide\u2010rich scaffold as well as resistance to proteolytic hydrolysis. These results broaden the scope of design strategies toward protein mimetics as well as folds and biological functions possible in such agents.<\/jats:p>","DOI":"10.1002\/cbic.202400951","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T11:34:26Z","timestamp":1734953666000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Structural and Functional Mimicry of the Antimicrobial Defensin Plectasin by Analogues with Engineered Backbone Composition"],"prefix":"10.1002","volume":"26","author":[{"given":"Thomas W.","family":"Harmon","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Pittsburgh  Pittsburgh PA 15260 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junming","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health Graduate School of Public Health University of Pittsburgh  Pittsburgh PA 15260 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew J.","family":"Gulewicz","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Pittsburgh  Pittsburgh PA 15260 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y. 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