Inactivation of the positive LuxR-type oligomycin biosynthesis regulators OlmRI and OlmRII increases avermectin production in Streptomyces avermitilis

Abstract

Oligomycins are a group of 26 macrocyclic lactones that exhibit broad biological activities, including antifungal, anticancer and nematocidal activities. Analysis of the oligomycin biosynthetic gene cluster (olm) in S. avermitilis revealed 2 tandem LuxR-type regulators, OlmRI (931 aa) and OlmRII (941 aa), with shared identity of 38%. Gene replacement of olmRI or olmRII abolished oligomycin production, and this production could be partially restored in the disruptants by introducing cloned olmRI and olmRII with their native promoters, demonstrating the essential role of OlmRI and OlmRII for oligomycin biosynthesis. Quantitative real-time RT-PCR analysis revealed that transcription of 14 olm genes was differentially affected by the deletion of olmRI and olmRII. Unexpectedly, avermectin production in both mutants was enhanced at least 4-fold. The identification of the positive cluster-situated regulators, OlmRI and OlmRII, paves the way for the transcriptional analysis of oligomycin biosynthesis and for the enhancement of oligomycin and avermectin production through regulator engineering. © 2011 Science China Press and Springer-Verlag Berlin Heidelberg.