Overproduction and identification of butyrolactones SCB1–8 in the antibiotic production superhost Streptomyces M1152

Abstract

Gamma-butyrolactones (GBLs) are signalling molecules that control antibiotic production in Streptomyces bacteria. The genetically engineered strain S. coelicolor M1152 was found to overproduce GBLs SCB1-3 as well as five novel GBLs named SCB4-8. Incorporation experiments using isotopically-labelled precursors confirmed the chemical structures of SCB1-3 and established those of SCB4-8.

Regulation of Antibiotic Production by Signaling Molecules in Streptomyces

“…The S. coelicolor M1152 is a derivative of S. coelicolor M145 lacking four biosynthetic gene clusters (BGCs) for the biosynthesis of actinorhodin (ACT), undecylprodigiosin (RED), calcium-dependent antibiotic (CDA) and coelimycin. It should be noted that the deletion of the coelimycin gene cluster included scbR2, which encodes a repressor of SCBs biosynthetic gene scbA, and thereby contributed to the overproduction of SCBs in S. coelicolor M1152 (Gomez-Escribano and Bibb, 2012; Sidda et al, 2016). In a BLAST survey, we found one to three afsAlike genes in each of nine Streptomyces genomes (Niu et al, 2016).…”

“…It is therefore necessary to identify more hormone-like signaling molecules. Currently, several approaches have been used to discover new signaling molecules in Streptomyces, including deletion of gene encoding repressor of signaling molecule biosynthetic gene (Sidda et al, 2016), bioassay using disruptants of known signaling molecule biosynthetic genes as indicator strains (Thao et al, 2017;Nguyen et al, 2018), and heterologous expression of putative signaling molecule biosynthetic genes in model microorganisms (Wang et al, 2018). These approaches will speed up the process of identifying new signaling molecules, and their signal transduction pathways.…”

“…GBLs, the largest group of these signaling molecules, share a characteristic 2,3-disubstituted GBL core skeleton but differ in the length, branching and stereochemistry of the acyl side chain (Takano, 2006). So far, a total of 19 GBLs have been identified in streptomycetes, including the A-factor from S. griseus, eight butanolides (SCB1-8) from Streptomyces coelicolor, five virginiae butanolides (VBs A-E) from Streptomyces virginiae, IM-2 from Streptomyces lavendulae, factor 1 from Streptomyces viridochromogenes, and three Gräfe's factors from Streptomyces bikinensis and Streptomyces cyaneofuscatus (Figure 1; Niu et al, 2016;Sidda et al, 2016). To gain insight to the distribution of GBLs, an A-factor-deficient mutant of S. griseus was used as an indicator strain to screen against 203 actinomycete strains.…”

“…Among the eight butanolides identified in the model organism S. coelicolor, SCB1-3 were identified in the 2000s (Takano et al, 2000;Hsiao et al, 2009). Recently, the engineered strain S. coelicolor M1152 was found to overproduce GBLs SCB1-3 as well as five novel GBLs designated as SCB4-8 (Sidda et al, 2016). The S. coelicolor M1152 is a derivative of S. coelicolor M145 lacking four biosynthetic gene clusters (BGCs) for the biosynthesis of actinorhodin (ACT), undecylprodigiosin (RED), calcium-dependent antibiotic (CDA) and coelimycin.…”

Identification of a butenolide signaling system that regulates nikkomycin biosynthesis in Streptomyces

“…This impedes the discovery of new signaling molecules and elucidation of their function. Since the first ␥-butyrolactone (GBL) signaling molecule, A-factor, was discovered in Streptomyces griseus, only 33 autoregulators have been identified in Streptomyces (1)(2)(3). They are classified into five groups, GBLs, furans, butenolides, PI factor, and N-methylphenylalanyl-dehydrobutyrine diketopiperazine, based on their structures.…”