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Without new agents to treat antibiotic\u2010resistant bacterial infections, mortality rates are predicted to reach 10 million people per year by 2050. Most antibiotics are derived from natural products (NPs) produced by bacteria; however, this resource was abandoned by industry because of high rediscovery rates. We are amid a natural product renaissance fuelled by inexpensive access to genome sequencing and sophisticated bioinformatic tools, which have highlighted that most of the biosynthetic pathways for NPs are not expressed in the laboratory. Here, we engineered the expression of a silent biosynthetic gene cluster harboured by an environmental isolate of\n                    <jats:italic>Streptomyces albidoflavus<\/jats:italic>\n                    . Using a bioinformatics\u2010guided approach, we isolated and structurally characterised a novel glycopeptide antibiotic (GPA) named biffamycin A, which is the smallest GPA known and harbours unprecedented 5\u2010chloro\u20104\u2010methoxy tryptophan and 3\u2010hydroxy(\u03b1\u2010D\u2010mannoysl)\u2010D\u2010lysine moieties. Biffamycin A possesses antimycobacterial and antistaphylococcal bioactivity, including against methicillin\u2010 and vancomycin\u2010resistant\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1002\/anie.202511349","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T09:19:42Z","timestamp":1778059182000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Discovery and Biosynthesis of the Novel Glycotetrapeptide Antibiotic Biffamycin A"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9628-895X","authenticated-orcid":false,"given":"Michael W.","family":"Brigham","sequence":"first","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5390-6020","authenticated-orcid":false,"given":"Edward S.","family":"Hems","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, John Innes Centre Norwich Research Park  Norwich UK"},{"name":"Centre For Microbial Interactions Norwich Research Park  Norwich UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6072-1895","authenticated-orcid":false,"given":"Daniel C. 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