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 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.