Isolation, Structure, and Absolute Stereochemistry of Platensimycin, A Broad Spectrum Antibiotic Discovered Using an Antisense Differential Sensitivity Strategy

Fatty acids are essential for survival of bacteria and are synthesized by a series of enzymes including the elongation enzymes, β-ketoacyl acyl carrier protein synthase I/II (FabF/B). Inhibition of fatty acid synthesis is one of the new targets for the discovery and development of antibacterial agen...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2006-09, Vol.128 (36), p.11916-11920
Main Authors: Singh, Sheo B, Jayasuriya, Hiranthi, Ondeyka, John G, Herath, Kithsiri B, Zhang, Chaowei, Zink, Deborah L, Tsou, Nancy N, Ball, Richard G, Basilio, Angela, Genilloud, Olga, Diez, Maria Teresa, Vicente, Francisca, Pelaez, Fernando, Young, Katherine, Wang, Jun
Format: Article
Language:English
Subjects:
Adamantane - chemistry
Adamantane - isolation & purification
Adamantane - pharmacology
Alicyclic compounds
Alicyclic compounds, terpenoids, prostaglandins, steroids
Aminobenzoates - chemistry
Aminobenzoates - isolation & purification
Aminobenzoates - pharmacology
Anilides - chemistry
Anilides - isolation & purification
Anilides - pharmacology
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - isolation & purification
Anti-Bacterial Agents - pharmacology
Chemistry
Crystallography, X-Ray
Exact sciences and technology
General and physical chemistry
Lipids
Models, Molecular
Molecular Conformation
Nuclear Magnetic Resonance, Biomolecular
Organic chemistry
Preparations and properties
Stereoisomerism
Streptomyces - chemistry
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Summary:Fatty acids are essential for survival of bacteria and are synthesized by a series of enzymes including the elongation enzymes, β-ketoacyl acyl carrier protein synthase I/II (FabF/B). Inhibition of fatty acid synthesis is one of the new targets for the discovery and development of antibacterial agents. Platensimycin (1a) is a novel broad spectrum Gram-positive antibiotic produced by Streptomyces platensis. It was discovered by target-based whole-cell screening strategy using antisense differential sensitivity assay. It inhibits bacterial growth by selectively inhibiting condensing enzyme FabF of the fatty acid synthesis pathway and was isolated by a two-step process, a capture step followed by reversed-phase HPLC. The structure was elucidated by 2D NMR methods and confirmed by X-ray crystallographic analysis of a bromo derivative. It was determined that potential reactivity of the enone moiety does not play a key role in the biological activity of platensimycin. However, cyclohexenone ring conformation renders for the stronger binding interaction with the enzyme. The isolation, structure elucidation, derivatization, and biological activity of 6,7-dihydroplatensimycin are described.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja062232p