Global negative regulation of Streptomyces coelicolor antibiotic synthesis mediated by an absA-encoded putative signal transduction system

Abstract

Streptomycete antibiotic synthesis is coupled to morphological differentiation such that antibiotics are produced as a colony sporulates. Streptomyces coelicolor produces several structurally and genetically distinct antibiotics. The S. coelicolor absA locus was defined by four UV-induced mutations that globally blocked antibiotic biosynthesis without blocking morphological differentiation. We show that the absA locus encodes a putative eubacterial two-component sensor kinase-response regulator system. All four mutations lie within a single open reading frame, designated absA1, which is predicted to encode a sensor histidine kinase. A second gene downstream of absA1, absA2, is predicted to encode the cognate response regulator. In marked contrast to the antibiotic-deficient phenotype of the previously described absA mutants, the phenotype caused by disruption mutations in the absA locus is precocious hyperproduction of the antibiotics actinorhodin and undecylprodigiosin. Precocious hyperproduction of these antibiotics is correlated with premature expression of XylE activity in a transcriptional fusion to an actinorhodin biosynthetic gene. We propose that the absA locus encodes a signal transduction mechanism that negatively regulates synthesis of the multiple antibiotics produced by S. coelicolor.

Genetic suppression analysis of non-antibiotic-producing mutants of the Streptomyces coelicolor absA locus

“…Escherichia coli DH5α (Gibco-BRL) was used for plasmid cloning. S. coelicolor and E. coli culture techniques were as previously described (Brian et al, 1996).…”

“…This locus was subsequently shown to encode a two-component signal transduction system (Brian et al, 1996) composed of AbsA1, a homologue of ' orthodox ' histidine kinase sensor-transmitter proteins, and AbsA2, a putative DNA-binding response regulator with the amino acid sequences conserved in ' orthodox ' response-regulator proteins (Parkinson, 1995 ;Stock et al, 1995). The absA locus regulates transcription of the actII-ORF4 and redD pathway-specific activators (Aceti & Champness, 1998).…”

“…The absA mutants isolated on the basis of their Abs − phenotype were shown, by marker rescue experiments (Brian et al, 1996), to carry mutations of the absA1 gene. In contrast, disruptions of the locus resulted in a phenotype of early onset enhanced antibiotic production.…”

“…This phenotype was associated with disruption of both absA1 and absA2 or of absA2 alone. Hence, we proposed (Brian et al, 1996) that the absA locus exerts a negative regulatory effect on antibiotic production and that the Abs − absA strains are mutationally locked into the negatively acting state.…”

Induction of antimicrobial activities in heterologous streptomycetes using alleles of the Streptomyces coelicolor gene absA1

“…6,7 AbsA2BP represses several biosynthetic gene clusters and absA1 mutations that impair AbsA2 phosphorylation enhance the expression of these clusters. 6,7 absA-like operons are found primarily in actinomycetes and are often embedded in the biosynthetic gene clusters of secondary metabolites, 8 perhaps suggesting that the regulation of secondary metabolism by this subfamily is a common phenomenon. We previously described two alleles of absA1 that enhance antibiotic production in S. coelicolor, the point mutant absA1H202A and the in-frame deletion mutant absA1del3/4.…”