Biosynthesis of fluopsin C, a copper-containing antibiotic from Pseudomonas aeruginosa

• Published in: Science (American Association for the Advancement of Science) Vol. 374; no. 6570; pp. 1005 - 1009
• Main Authors: Patteson, Jon B, Putz, Andrew T, Tao, Lizhi, Simke, William C, Bryant, 3rd, L Henry, Britt, R David, Li, Bo
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 19.11.2021
• Subjects: Anti-Bacterial Agents - biosynthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; Bacteria; Bacteria - drug effects; Biological activity; Biosynthesis; Biosynthetic Pathways; Carboxyl group; Chemical synthesis; Coordination compounds; Copper; Copper - analysis; Copper - metabolism; Copper - pharmacology; Copper compounds; Copper converters; Cysteine; Decarboxylation; Drug Resistance, Bacterial; Electron Spin Resonance Spectroscopy; Enzymes; Genes, Bacterial; Hydroxylation; Iron; Metal ions; Metals; Methyltransferase; Microbial Sensitivity Tests; Molecular Structure; Natural products; Operon; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - enzymology; Pseudomonas aeruginosa - genetics; Pseudomonas aeruginosa - metabolism; Transition metals; Virulence
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.abj6749

Metal-binding natural products contribute to metal acquisition and bacterial virulence, but their roles in metal stress response are underexplored. We show that a five-enzyme pathway in synthesizes a small-molecule copper complex, fluopsin C, in response to elevated copper concentrations. Fluopsin C is a broad-spectrum antibiotic that contains a copper ion chelated by two minimal thiohydroxamates. Biosynthesis of the thiohydroxamate begins with cysteine and requires two lyases, two iron-dependent enzymes, and a methyltransferase. The iron-dependent enzymes remove the carboxyl group and the α carbon from cysteine through decarboxylation, N-hydroxylation, and methylene excision. Conservation of the pathway in and other bacteria suggests a common role for fluopsin C in the copper stress response, which involves fusing copper into an antibiotic against other microbes.