Background: NsrR family proteins are [2Fe-2S] or [4Fe-4S] cluster-containing global regulators.Results: Streptomyces coelicolor NsrR regulates only three genes, and it is the [4Fe-4S] form of the protein that binds tightly to NsrR-regulated promoters.Conclusion: [4Fe-4S] NsrR has a specialized function associated only with nitric oxide stress response.Significance: Members of the NsrR family are most likely all [4Fe-4S] proteins.

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MtrAB is a highly conserved two-component system implicated in the regulation of cell division in the Actinobacteria. It coordinates DNA replication with cell division in the unicellular Mycobacterium tuberculosis and links antibiotic production to sporulation in the filamentous Streptomyces venezuelae. Chloramphenicol biosynthesis is directly regulated by MtrA in S. venezuelae and deletion of mtrB constitutively activates MtrA and results in constitutive over-production of chloramphenicol. Here we report that in Streptomyces coelicolor, MtrA binds to sites upstream of developmental genes and the genes encoding ActII-1, ActII-4 and RedZ, which are cluster-situated regulators of the antibiotics actinorhodin (Act) and undecylprodigiosin (Red). Consistent with this, deletion of mtrB switches on the production of Act, Red and streptorubin B, a product of the Red pathway. Thus, we propose that MtrA is a key regulator that links antibiotic production to development and can be used to upregulate antibiotic production in distantly related streptomycetes.

Streptomyces bacteria make numerous secondary metabolites, including half of all 25 known antibiotics. Production is coordinated with their complex life cycles but the regulators 26 that coordinate development with antibiotic biosynthesis are largely unknown. This is 27 important to understand because most Streptomyces secondary metabolites are not produced 28 under laboratory conditions and unlocking the 'cryptic' biosynthetic gene clusters (BGCs) is a 29 major focus for antibiotic discovery. Here we characterise the highly conserved actinobacterial 30 response regulator MtrA in Streptomyces species. MtrA is essential and regulates cell cycle 31 progression in Mycobacterium tuberculosis. We show that MtrA is also essential in 32 Streptomyces venezuelae where it controls genes required for DNA replication and cell 33 division. MtrA also directly regulates the expression of genes in >70% of its BGCs and 34 artificially activating MtrA switches on the production of antibiotics in S. coelicolor and S.