Regulatory role of TipA in Streptomyces under thiopeptide and metal stress

Streptomycetes, known as producers of various secondary metabolites, developed numerous mechanisms including the thiopeptide-binding transcriptional regulator TipA to cope with environmental stressors. Deletion of tipA in the metal sensitive model strain Streptomyces coelicolor A3(2) and the metal tolerant Streptomyces mirabilis P16B-1 was shown to impact these strains in several ways. Loss of TipA impacted survival of the two evaluated Streptomycetes, particularly S. coelicolor A3(2), when exposed to thiostrepton (Ts). However, P16B-1 responded with more extensive gene expression regulation than A3(2) upon Ts stress, indicating that metal exposure leads to development of various mechanisms to tolerate Ts stress. Furthermore, the combined Ts and metal stress revealed induction of co-selection of resistance mechanisms with A3(2) ΔtipA and P16B-1 (wild type and ΔtipA) tolerating higher Ts concentrations when exposed to subinhibitory Ni concentrations. Metal homeostasis was differently affected in the ΔtipA strain of A3(2) under Ts stress and for P16B-1 under nickel stress. The transcription of cobalamin (B12) synthesis genes was shown to be differently regulated in the ΔtipA strains, specifically for A3(2) under Ni stress and in P16B-1 under Ts stress. B12 extraction showed a negative influence of metal stress on the cellular B12 content in A3(2), however similarly for wild type and the ΔtipA strain. Inhibition of actinorhodin production was observed in A3(2) ΔtipA. Proteome analysis showed that the strain displayed an altered abundance of proteins involved in biosynthesis of several antibiotics, siderophores and a carotenoid as well as a decrease of siderophore transporter. Moreover, abundance of various regulatory proteins, such as transcriptional regulators AbaA, of the GntR family and WhiB as well as ECF-subfamily sigma factors was affected.