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Today, however, the rediscovery of known compounds is a significant hurdle to developing new antimicrobials. Here we use a genome mining and synthetic biology approach to discover the ambocidins: calcium\u2010dependent lipodepsipeptides that are active against drug\u2010resistant Gram\u2010positive pathogens. By cloning a silent biosynthetic gene cluster (the\n                    <jats:italic>amb<\/jats:italic>\n                    cluster) from\n                    <jats:italic>Streptomyces ambofaciens<\/jats:italic>\n                    ATCC 2387 and integrating this into the chromosome of\n                    <jats:italic>Streptomyces avermitilis<\/jats:italic>\n                    we induce expression of ambocidin A and B: two new N\n                    <jats:sup>\u03f5<\/jats:sup>\n                    \u2010hydroxyarginine\u2010containing cyclic lipodepsipeptides active against drug\u2010resistant Gram\u2010positive pathogens. Using a panel of\n                    <jats:italic>Streptomyces<\/jats:italic>\n                    host strains, we show that the choice of heterologous host is critical for producing the biologically active compounds, and that inappropriate host choice leads to aberrant production inactive derivatives. We show that N\n                    <jats:sup>\u03f5<\/jats:sup>\n                    \u2010hydroxyarginine is the product of a heme\u2010dependent oxygenase and that it enhances biological activity. Ambocidin A inhibits cell wall biosynthesis by binding to Lipid II at a different site than vancomycin. Furthermore, unlike daptomycin, ambocidin A retains potent antimicrobial activity in the presence of lung surfactant, giving it the potential to treat bacterial pneumonia. Our work expands the family of calcium\u2010dependent lipopeptide antibiotics with a new member exhibiting a distinct mechanism of action.\n                  <\/jats:p>","DOI":"10.1002\/anie.202410286","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T23:26:14Z","timestamp":1724369174000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Calcium\u2010Dependent Lipopeptide Antibiotics against Drug\u2010Resistant Pathogens Discovered via Host\u2010Dependent Heterologous Expression of a Cloned Biosynthetic Gene Cluster"],"prefix":"10.1002","volume":"63","author":[{"given":"Hung\u2010En","family":"Lai","sequence":"first","affiliation":[{"name":"School of Biological Sciences Victoria University of Wellington  6012 Wellington New Zealand"},{"name":"Maurice Wilkins Centre for Molecular Biodiscovery  1010 Auckland New Zealand"},{"name":"Centre for Biodiscovery School of Biological Sciences Victoria University of Wellington  6012 Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V. 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