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Butuanimides, Fatty Acid Synthesis-Inhibiting Antibiotics from Symbiotic Bacteria

Year: 2026

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide With the ongoing antibiotic drug resistance crisis, new molecules with new mechanisms of action are essential. Here, we characterized quorum sensing-regulated butuanimides from symbiotic γ-proteobacteria, Teredinibacter sp. 2052S, which kill Gram-positive bacterial and human cells with micromolar and submicromolar potencies, respectively. Butuanimides share a peptide-imide moiety with andrimid-class antibiotics that target bacterial acetyl-CoA carboxylase (ACC), the rate-limiting step in fatty acid biosynthesis. Similarly, site-directed mutagenesis in Acinetobacter baylyi identified the ACC carboxyl transferase (CT) subunit as responsible for butuanimide antibacterial activity. The andrimid-like peptide-imide moiety is attached to a longer, halogenated polyene chain that initiates with an unusual starter unit likely derived from phenylalanine. The resulting epoxyquinone is unstable in solution over a period of hours to days, enabling redox control of antibiotic action. Comparison of the hybrid polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) biosynthetic gene clusters of butuanimides and andrimid suggests the repurposing of a key phenylalanine-derived motif. The butuanimide structures link the thailandamide- and andrimid-class ACC inhibitors, which should aid ongoing efforts in the development of ACC inhibitors to treat multidrug-resistant infections.

Source: ACS Chemical Biology

DOI: 10.1021/acschembio.6c00130