Development of the ability to produce secondary metabolites in Streptomyces through the acquisition of erythromycin resistance

Members of the genus Streptomyces are gram-positive filamentous bacteria that produce various secondary metabolites, which are exemplified by antibiotics. Because more than two-thirds of clinically useful antibiotics are produced from Streptomyces,¹ members of this genus are of high pharmacological and industrial interest. Additionally, recent genome-sequencing projects have revealed that many biosynthetic gene clusters, producing unknown secondary metabolites, exist in Streptomyces genomes.^{2, 3, 4} The exploitation of the genomic potential of Streptomyces may lead to the isolation of new biologically active compounds.^{5, 6} Therefore, it is extremely important for antibiotic discovery research to investigate their unexploited abilities to produce secondary metabolites and to clarify their activation mechanism. We previously demonstrated a method for activating unexpressed or poorly expressed Streptomyces genes to synthesize secondary metabolites through a mutation that confers resistance to drugs targeting the RNA polymerase and/or ribosomes.^{7, 8, 9} This led to the discovery of piperidamycin, a novel antibiotic produced by Streptomyces sp. 631689, which rarely produces antibiotics in any type of culture media.¹⁰ Here, we describe a new technique for advanced utilization of the above-mentioned method to take complete advantage of the ability of Streptomyces to produce secondary metabolites.

Erythromycin is a macrolide antibiotic that inhibits protein synthesis by binding to the bacterial 50S ribosomal subunit. Previous studies have demonstrated that generating a mutation that confers resistance to a drug, such as rifampicin, streptomycin, gentamicin, paromomycin or thiostrepton, is an effective approach to increasing the production of the blue-pigmented antibiotic actinorhodin (ACT) in Streptomyces coelicolor A3(2) and Streptomyces lividans.^{9, 11, 12, 13}S. coelicolor A3(2) and S. lividans are well-characterized strains of Streptomyces from a physiological and genetic viewpoint; however, the effects of an erythromycin resistance mutation on antibiotic production in S. coelicolor A3(2) and S. lividans have not been assessed. Therefore, we examined whether the acquisition of erythromycin resistance enables S. coelicolor A3(2) and S. lividans to overproduce antibiotics.

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