Impact on Multiple Antibiotic Pathways Reveals MtrA as a Master Regulator of Antibiotic Production in Streptomyces spp. and Potentially in Other Actinobacteria

Regulation of antibiotic production by is complex. We report that the response regulator MtrA is a master regulator for antibiotic production in Deletion of MtrA altered production of actinorhodin, undecylprodigiosin, calcium-dependent antibiotic, and the yellow-pigmented type I polyketide and resulted in altered expression of the corresponding gene clusters in Integrated and analyses identified MtrA binding sites upstream of , , and and between and MtrA disruption also led to marked changes in chloramphenicol and jadomycin production and in transcription of their biosynthetic gene clusters ( and , respectively) in , and MtrA sites were identified within and MtrA also recognized predicted sites within the avermectin and oligomycin pathways in and in the validamycin gene cluster of The regulator GlnR competed for several MtrA sites and impacted production of some antibiotics, but its effects were generally less dramatic than those of MtrA. Additional potential MtrA sites were identified in a range of other antibiotic biosynthetic gene clusters in species and other actinobacteria. Overall, our study suggests a universal role for MtrA in antibiotic production in and potentially other actinobacteria. In natural environments, the ability to produce antibiotics helps the producing host to compete with surrounding microbes. In , increasing evidence suggests that the regulation of antibiotic production is complex, involving multiple regulatory factors. The regulatory factor MtrA is known to have additional roles beyond controlling development, and using bioassays, transcriptional studies, and DNA-binding assays, our study identified MtrA recognition sequences within multiple antibiotic pathways and indicated that MtrA directly controls the production of multiple antibiotics. Our analyses further suggest that this role of MtrA is evolutionarily conserved in species, as well as in other actinobacterial species, and also suggest that MtrA is a major regulatory factor in antibiotic production and in the survival of actinobacteria in nature.