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The genus <jats:italic>Streptomyces<\/jats:italic> in particular is able to produce a wide range of antimicrobial products due to the large number of biosynthetic gene clusters (BGCs) in its genome. However, not all BGCs are expressed under laboratory conditions. In this work, deletion of the gene <jats:italic>wblA<\/jats:italic>, encoding a global regulator of natural product biosynthesis and morphogenesis in <jats:italic>Streptomyces<\/jats:italic>, led to the production of a novel natural product, olikomycin A, in <jats:italic>Streptomyces ghanaensis<\/jats:italic> ATCC 14672. Complete structure elucidation revealed that olikomycin A belongs to a class of calcium\u2010dependent antibiotics known as non\u2010ribosomal peptide synthetase (NRPS)\u2010encoded acidic lipopeptides. These compounds exhibit remarkable antimicrobial activity in the presence of calcium. Insights into olikomycin A biosynthesis were provided by whole genome sequencing and gene inactivation studies, while bioactivity assays showed strong inhibition of the growth of multidrug\u2010resistant Gram\u2010positive pathogens via disrupting cell membrane integrity. Olikomycin A shows an antibiotic profile similar to that of daptomycin, which is already in clinical use.<\/jats:p>","DOI":"10.1002\/chem.202403985","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T05:34:53Z","timestamp":1733117693000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Olikomycin A\u2013A Novel Calcium\u2010Dependent Lipopeptide with Antibiotic Activity Against Multidrug\u2010Resistant Bacteria"],"prefix":"10.1002","volume":"31","author":[{"given":"Roman","family":"Makitrynskyy","sequence":"first","affiliation":[{"name":"Institute for Pharmaceutical Biology and Biotechnology University of Freiburg  Stefan-Meier-Str. 19 79104 Freiburg Germany"},{"name":"Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures GmbH  Inhoffenstra\u00dfe 7B 38124 Braunschweig 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