Waldiomycin, a novel WalK-histidine kinase inhibitor from Streptomyces sp MK844-mF10

WalK, a histidine kinase, and WalR, a response regulator, make up a two-component signal transduction system that is indispensable for the cell-wall metabolism of low GC Gram-positive bacteria. WalK inhibitors are likely to show bactericidal effects against methicillin-resistant Staphylococcus aureus. We discovered a new WalK inhibitor, designated waldiomycin, by screening metabolites from actinomycetes. Waldiomycin belongs to the family of angucycline antibiotics and is structurally related to dioxamycin. Waldiomycin inhibits WalK from S. aureus and Bacillus subtilis at IC(50)s 8.8 and 10.2 mu M, respectively, and shows antibacterial activity with MICs ranging from 4 to 8 mu g ml(-1) against methicillin-resistant S. aureus and B. subtilis.