Avenolide, a Streptomyces hormone controlling antibiotic production in Streptomyces avermitilis

Abstract

Gram-positive bacteria of the genus Streptomyces are industrially important microorganisms, producing >70% of commercially important antibiotics. The production of these compounds is often regulated by low-molecular-weight bacterial hormones called autoregulators. Although 60% of Streptomyces strains may use γ-butyrolactone–type molecules as autoregulators and some use furan-type molecules, little is known about the signaling molecules used to regulate antibiotic production in many other members of this genus. Here, we purified a signaling molecule (avenolide) from Streptomyces avermitilis —the producer of the important anthelmintic agent avermectin with annual world sales of $850 million—and determined its structure, including stereochemistry, by spectroscopic analysis and chemical synthesis as (4 S ,10 R )-10-hydroxy-10-methyl-9-oxo-dodec-2-en-1,4-olide, a class of Streptomyces autoregulator. Avenolide is essential for eliciting avermectin production and is effective at nanomolar concentrations with a minimum effective concentration of 4 nM. The aco gene of S. avermitilis, which encodes an acyl-CoA oxidase, is required for avenolide biosynthesis, and homologs are also present in Streptomyces fradiae , Streptomyces ghanaensis , and Streptomyces griseoauranticus , suggesting that butenolide-type autoregulators may represent a widespread and another class of Streptomyces autoregulator involved in regulating antibiotic production.

Total synthesis and absolute configuration of avenolide, extracellular factor in Streptomyces avermitilis

“…In contrast, the rAvaR1-ligand activities of the C10-epimer (19), the C4-epimer (22) and the 10-deoxy avenolide (28) demonstrated only one-half, one twenty-fifth and one hundredth of the activity of the natural product, respectively. 6 It can therefore be concluded that the stereochemistry at C4 and C10, and the presence of the hydroxyl group at C10, are important to the activity of avenolide as a rAvaR1 ligand.…”

“…6 Supplementary Information accompanies the paper on The Journal of Antibiotics website (http://www.nature.com/ja) Total synthesis and absolute configuration of avenolide…”

“…To identify the extracellular factor(s) controlling avermectin production in Streptomyces avermitilis, about 1 mg of the extracellular factor from 1000 l of culture filtrate was isolated and purified by chromatographic separation steps. 6 Since spectroscopic analyses of the extracellular factor purified have elucidated that the factor is a new butenolide structure including two stereogenic centers (Scheme 1) but not gbutyrolactone structure, the extracellular factor is named as ''avenolide.'' The absolute configuration could not be elucidated, however, due to the trace quantities isolated and the presence of contaminants.…”

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

“…PI factor enhances pimaricin production in S. natalensis (239). Avenolide is required at nanomolar concentrations for the onset of avermectin biosynthesis in S. avermitilis (238) (avenolide homologs are also found in S. fradiae, Streptomyces ghanaensis, and S. griseoauranticus).…”

Pleiotropic Control of Secondary Metabolism and Morphological Development by KsbC, a Butyrolactone Autoregulator Receptor Homologue in Kitasatospora setae

“…The single afsA family genes afsA, scbA, and avaA (17) are present on the genomes of S. griseus, S. coelicolor A3(2), and S. avermitilis, respectively. The flanking region of scbA has scbR (a receptor of an SCB1 autoregulator), and that of avaA has avaL1/L2 (receptors of an unidentified molecule), whereas the afsA locus is 3.9 Mb away from the locus of arpA (A-factor receptor gene).…”