<jats:title>Abstract</jats:title><jats:p>The large number of sequenced bacterial genomes provides the opportunity to bioinformatically identify rich natural product sources among previously neglected microbial groups. Testing this discovery strategy, unusually high biosynthetic potential was suggested for the Oceanospirillales member <jats:italic>Gynuella sunshinyii</jats:italic>, a Gram‐negative marine bacterium from the rhizosphere of the halophilic plant <jats:italic>Carex scabrifolia</jats:italic>. Its genome contains numerous unusual biosynthetic gene clusters for diverse types of metabolites. Genome‐guided isolation yielded representatives of four different natural product classes, of which only alteramide A was known. Cytotoxic lacunalides were identified as products of a giant <jats:italic>trans</jats:italic>‐acyltransferase polyketide synthase gene cluster, one of six present in this strain. Cytological profiling against HeLa cells suggested that lacunalide A disrupts CDK signaling in the cell cycle. In addition, chemical studies on model compounds were conducted, suggesting the structurally unusual ergoynes as products of a conjugated diyne–thiourea cyclization reaction.