Antimitotic rhizoxin derivatives from a cultured bacterial endosymbiont of the rice pathogenic fungus Rhizopus microsporus.
The potent antimitotic polyketide macrolide rhizoxin, the causal agent of rice seedling blight, is not produced by the fungus Rhizopus microsporus, as has been believed for over two decades, but by endosymbiotic bacteria that reside within the fungal mycelium. Here we report the successful isolation and large-scale fermentation of the bacterial endosymbiont ("Burkholderia rhizoxina") in pure culture, which resulted in a significantly elevated (10x higher) production of antimitotics. In addition to several known rhizoxin derivatives, numerous novel natural and semisynthetic variants were isolated, and their structures were fully elucidated. Cell-based assays as well as tubulin binding experiments revealed that methylated seco-rhizoxin derivatives are 1000-10000 times more active than rhizoxin and thus rank among the most potent antiproliferative agents known to date. Furthermore, more stable didesepoxy rhizoxin analogues were obtained by efficiently inhibiting a putative P-450 monooxygenase involved in macrolide tailoring.
Scherlach
Kirstin
K
Leibniz-Institute for Natural Product Research and Infection Biology, Jena, Germany.
Partida-Martinez
Laila P
LP
Dahse
Hans-Martin
HM
Hertweck
Christian
C
D000818:Animals; D050256:Antimitotic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D019117:Burkholderia / Q000302:isolation & purification / Q000378:metabolism / Q000472:pathogenicity; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005347:Fibroblasts / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D018942:Macrolides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D051379:Mice; D008868:Microtubule Proteins / Q000737:chemistry; D015394:Molecular Structure; D012275:Oryza / Q000382:microbiology*; D012233:Rhizopus / Q000302:isolation & purification / Q000378:metabolism / Q000472:pathogenicity; D013329:Structure-Activity Relationship; D013559:Symbiosis
D050256:Antimitotic Agents; D018942:Macrolides; D008868:Microtubule Proteins; C041443:rhizoxin