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New antibiotics with novel mechanisms of action are urgently needed to combat bacterial resistance. Bacterial lipopeptides, which are produced by modular enzyme complexes known as bacterial nonribosomal peptide synthetases (NRPS), are a promising source of such antibiotics as they can inhibit bacterial growth through diverse mechanisms. However, the biosynthetic gene clusters (BGCs) encoding NRPS are often silent in laboratory-grown bacteria. In a new study, Wang et al. use a pipeline of bioinformatics and synthetic chemistry techniques to predict and synthesize a lipopeptide antibiotic with a novel mechanism of action using the genomic information encoded in a BGC.