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, beta-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.
Singh
Sheo B
SB
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. sheo_singh@merck.com
Jayasuriya
Hiranthi
H
Ondeyka
John G
JG
Herath
Kithsiri B
KB
Zhang
Chaowei
C
Zink
Deborah L
DL
Tsou
Nancy N
NN
Ball
Richard G
RG
Basilio
Angela
A
Genilloud
Olga
O
Diez
Maria Teresa
MT
Vicente
Francisca
F
Pelaez
Fernando
F
Young
Katherine
K
Wang
Jun
J
D000218:Adamantane / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D062365:Aminobenzoates / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D000813:Anilides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism; D013302:Streptomyces / Q000737:chemistry*
D062365:Aminobenzoates; D000813:Anilides; D000900:Anti-Bacterial Agents; D000218:Adamantane; C510909:platensimycin