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

Comparative genome sequencing analysis of a lincomycin-resistant strain ofStreptomyces coelicolor A3(2) and the wild-type strain identified a novel mutation conferring a high level of lincomycin resistance. Surprisingly, the new mutation was an in-frame DNA deletion in the genesSCO4597 andSCO4598 , resulting in formation of the hybrid genelinR. SCO4597 andSCO4598 encode two histidine kinases, which together withSCO4596 , encoding a response regulator, constitute a unique two-component system. Sequence analysis indicated that these three genes and their arrangement patterns are ubiquitous among allStreptomyces genomes sequenced to date, suggesting these genes play important regulatory roles. Gene replacement showed that this mutation was responsible for the high level of lincomycin resistance, the overproduction of the antibiotic actinorhodin, and the enhanced morphological differentiation of this strain. Moreover, heterologous expression of the hybrid genelinR inEscherichia coli conferred resistance to lincomycin in this organism. Introduction of the hybrid genelinR in variousStreptomyces strains by gene engineering technology may widely activate and/or enhance antibiotic production.