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

Abstract

The bacterial genus Streptomyces is endowed with a remarkable secondary metabolism that generates an enormous number of bioactive small molecules. Many of these genetically encoded small molecules are used as antibiotics, anticancer agents and as other clinically relevant therapeutics. The rise of resistant pathogens has led to calls for renewed efforts to identify antimicrobial activities, including expanded screening of streptomycetes. Indeed, it is known that most strains encode 420 secondary metabolites and that many, perhaps most of these, have not been considered for their possible therapeutic use. One roadblock is that many strains do not express their secondary metabolic gene clusters efficiently under laboratory conditions. As one approach to this problem, we have used alleles of a pleiotropic regulator of secondary metabolism from Streptomyces coelicolor to activate secondary biosynthetic gene clusters in heterologous streptomycetes. In one case, we demonstrate the activation of pulvomycin production in S. flavopersicus, a metabolite not previously attributed to this species. We find that the absA1-engineered strains produced sufficient material for purification and characterization. As a result, we identified new, broad-spectrum antimicrobial activities for pulvomycin, including a potent antimicrobial activity against highly antibioticresistant Gram-negative and Gram-positive pathogens.

Novel Two-Component Systems Implied in Antibiotic Production in Streptomyces coelicolor

“…This fact makes this system extremely interesting since it could be used to overproduce clinical useful antibiotics by expressing abrA1/A2 alleles in heterologous streptomycetes as has been recently reported for the system AbsA1/A2 [30]. Interestingly, this system only has an orthologue in S.lividans being absent in all the other Streptomyces species sequenced to date.…”

Identification of a Novel Lincomycin Resistance Mutation Associated with Activation of Antibiotic Production in Streptomyces coelicolor A3(2)

“…S. coelicolor A3 (2) is enriched in two-component systems, having 67 gene sets in its genome (6). Several of these gene sets, including those coding for the CutR-S, AbsA1-A2, AbrA1-A2, and AfsQ1-Q2-SigQ proteins, have been characterized biochemically (25,(35)(36)(37). The dual two-component system composed of SCO4596-SCO4597-SCO4598 is one of the very few that regulates both antibiotic production and morphological differentiation, as demonstrated by knockout experiments (25).…”

An ecological perspective of microbial secondary metabolism

“…As a result there have been several efforts to attempt to 'unlock' the chemical diversity capacity of producing cells (e.g. [22,23]). In fact as anyone working in the field quickly recognizes, most secondary metabolites are produced by wild-type organisms in very low quantities and frequently the molecules adhere to producer cells rather than readily diffuse into the medium.…”