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Butuanimides, Fatty Acid Synthesis-Inhibiting Antibiotics from Symbiotic Bacteria
Bailey W Miller1, Albebson L Lim1, Jeannie Bailey2
1Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.
ACS Chemical Biology
|April 28, 2026
Summary
New butuanimide antibiotics from bacteria target acetyl-CoA carboxylase (ACC), crucial for fatty acid synthesis. These molecules show potent activity against Gram-positive bacteria and offer a novel approach to combat antibiotic resistance.
Area of Science:
- Microbiology
- Biochemistry
- Medicinal Chemistry
Background:
- The rise of antibiotic resistance necessitates novel antimicrobial agents with unique mechanisms of action.
- Quorum sensing (QS) regulates the production of various bioactive molecules in bacteria, including antibiotics.
Purpose of the Study:
- To characterize novel butuanimides produced by symbiotic γ-proteobacteria *Teredinibacter* sp. 2052S.
- To elucidate the mechanism of action and biosynthetic origins of butuanimides.
Main Methods:
- Isolation and structural characterization of butuanimides.
- Site-directed mutagenesis in *Acinetobacter baylyi* to identify the target protein.
- Bioinformatic analysis of hybrid polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) gene clusters.
Main Results:
- Butuanimides exhibit potent antibacterial activity against Gram-positive bacteria and cytotoxicity towards human cells.
- The antibacterial activity is attributed to the inhibition of acetyl-CoA carboxylase (ACC), specifically the carboxyl transferase (CT) subunit.
- Butuanimides possess a unique structure featuring a peptide-imide moiety linked to a halogenated polyene chain, with an unusual phenylalanine-derived starter unit.
- The epoxyquinone structure is unstable, allowing for redox-controlled antibiotic action.
Conclusions:
- Butuanimides represent a new class of ACC inhibitors with potential for treating multidrug-resistant infections.
- The study reveals the repurposing of a phenylalanine-derived motif in the biosynthesis of butuanimides, linking thailandamide and andrimid classes of ACC inhibitors.
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