Disruption of a methyltransferase gene in actinomycin G gene cluster in Streptomyces iakyrus increases the production of phenazinomycin

Abstract

Phenazinomycin is a hybrid natural product consisting of two chemical entities, a phenazine and a cyclic terpenoid. Phenazinomycin exhibits potent activity against murine tumors and adriamycin-resistant P388 leukemia cells. Streptomyces iakyrus DSM 41873 is known to produce five actinomycin G2-G6. In the previous study, we identified the gene cluster directing the biosynthesis of actinomycin G2-G4. Inactivation of acmG5′ gene in the actinomycin G gene cluster in S. iakyrus completely abolished the production of actinomycin G. Metabolic profiling, chemical isolation, and structural elucidation of the resulting mutant SIAΔacmG5′ showed a previously unnoticed metabolite phenazinomycin in S. iakyrus. In silico analysis identified a hybrid biosynthetic gene cluster in the genome of S. iakyrus that could be responsible for the biosynthesis of phenazinomycin. It is proposed that the perturbation of actinomycin G to enhance the phenazinomycin production in the mutant may result from the lifted competition of chorismate, the common precursor of the biosynthetic pathways of these two structurally unrelated natural products. Disruption of the synthesis of actinomycin G, potent anticancer agent, in the soil bacterium Streptomyces iakyrus, results in enhanced production of previously unreported and structurally unrelated natural product phenazinomycin, an antibiotic and anticancer agent. © 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.