Thuggacins, macrolide antibiotics active against Mycobacterium tuberculosis: isolation from myxobacteria, structure elucidation, conformation analysis and biosynthesis.
Two novel antibiotics, thuggacin A (1) and B (2), were isolated from the myxobacterium Sorangium cellulosum. 1 and 2 are unique thiazole-containing macrolides with side chains on both sides of the lactone group. Upon standing in solution, thuggacin A (1) rearranges by acyl migration of the lactone group to give a mixture with thuggacins B (2) and C (3). NOEs and vicinal coupling constants within the lactone ring provided distinct data for the generation of a structure model by PM3 calculations, which allowed an analysis of the conformation in solution and the relative configuration of six asymmetric centres. A minor sorangium metabolite was identified as 13-methyl-thuggacin A (4). Furthermore, two natural thuggacin variants, 5 and 6, were found in another myxobacterium, Chondromyces crocatus. In these variants, one side chain is replaced by a methyl group and a hydroxy group is repositioned to give a primary alcohol at the former methyl site, in an alpha position with respect to the thiazole ring. 1 proved to be active against clinical isolates and reference strains of Mycobacterium tuberculosis. Preliminary studies on the mechanism of action indicate inhibition of the cellular electron-transport chain.
Steinmetz
Heinrich
H
Helmholtz Centre for Infection Research, Research Group Microbial Drugs, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
Irschik
Herbert
H
Kunze
Brigitte
B
Reichenbach
Hans
H
Höfle
Gerhard
G
Jansen
Rolf
R
D000995:Antitubercular Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism; D018942:Macrolides / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D009231:Myxococcales / Q000737:chemistry* / Q000378:metabolism
D000995:Antitubercular Agents; D018942:Macrolides; C523035:thuggacin A; C523034:thuggacin B; C523033:thuggacin C