Total Synthesis of Albicidin: A Lead Structure from Xanthomonas albilineans for Potent Antibacterial Gyrase Inhibitors

• Published in: Angewandte Chemie (International ed.) Vol. 54; no. 6; pp. 1969 - 1973
• Main Authors: Kretz, Julian, Kerwat, Dennis, Schubert, Vivien, Grätz, Stefan, Pesic, Alexander, Semsary, Siamak, Cociancich, Stéphane, Royer, Monique, Süssmuth, Roderich D.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 02.02.2015; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: albicidin; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; Antiinfectives and antibacterials; Bacteria; Chemistry; Chemistry, Multidisciplinary; DNA Gyrase - drug effects; Drugs; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; gyrase; Inhibitors; Molecular Structure; Organic Chemicals - chemistry; Organic Chemicals - pharmacology; para-aminobenzoic acid; Peptides; Physical Sciences; Profiling; Science & Technology; Synthesis; total synthesis; Xanthomonas - chemistry; Xanthomonas albilineans; ASPARAGINE; SOLID-PHASE; peptides; NO ESKAPE; albicidin; gyrase; para-aminobenzoic acid; GRAM-NEGATIVE BACTERIA; BAD BUGS; CRESCENT OLIGOAMIDES; HELICAL POLYPEPTIDES; DNA GYRASE; RESISTANCE; total synthesis; INFECTIOUS-DISEASES SOCIETY
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201409584

The peptide antibiotic albicidin, which is synthesized by the plant pathogenic bacterium Xanthomonas albilineans, displays remarkable antibacterial activity against various Gram‐positive and Gram‐negative microorganisms. The low amounts of albicidin obtainable from the producing organism or through heterologous expression are limiting factors in providing sufficient material for bioactivity profiling and structure–activity studies. Therefore, we developed a convergent total synthesis route toward albicidin. The unexpectedly difficult formation of amide bonds between the aromatic amino acids was achieved through a triphosgene‐mediated coupling strategy. The herein presented synthesis of albicidin confirms the previously determined chemical structure and underlines the extraordinary antibacterial activity of this compound. The synthetic protocol will provide multigram amounts of albicidin for further profiling of its drug properties. New antibiotics are urgently needed in view of bacterial resistance to established drugs. Albicidin shows activity against various Gram‐negative and Gram‐positive bacteria, thus making it a promising lead candidate for drug development. The first total synthesis of albicidin was achieved through a convergent synthetic approach that is applicable to the production of derivatives for structure–activity studies.