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

Abstract

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 IC50s 8.8 and 10.2 μM, respectively, and shows antibacterial activity with MICs ranging from 4 to 8 μg ml(-1) against methicillin-resistant S. aureus and B. subtilis.

Virulence Factor Targeting of the Bacterial Pathogen Staphylococcus aureus for Vaccine and Therapeutics

“…Similar research was also undertaken by Igarashi et al The authors were also able to isolate a novel species of Streptomyces dubbed MK844-mF10 that produced an active compound against the WalK protein from B. subtilis [196]. The compound, dubbed waldiomycin bears structural similarity to diozamycin and was also active against several strains of S. aureus including two different MRSA strains with a MIC of 16 μg/mL [196].…”

“…TCS inhibiton has also been shown to cause rapid bactericidal effects [194–196]. Specifically targeting the WalK/WalR (YycG/YycF) two component system which is essential to cell wall metabolism in S. aureus results in death of the bacteria [194–196].…”

“…Specifically targeting the WalK/WalR (YycG/YycF) two component system which is essential to cell wall metabolism in S. aureus results in death of the bacteria [194–196]. Work by Okada et al isolated a natural product from Streptomyces sp.…”

“…The compound, dubbed waldiomycin bears structural similarity to diozamycin and was also active against several strains of S. aureus including two different MRSA strains with a MIC of 16 μg/mL [196]. Waldiomycin was determined to prevent the autophosphorylation of WalK for both the B. subtilis and S. aureus purified protein product [196]. …”

Bacterial Histidine Kinases as Novel Antibacterial Drug Targets

“…SBVS has identified a range of TCSs inhibitors. In SBVS targeted against TCSs, the most successful screens have found inhibitors that target the conserved catalytic ATP-binding CA domain of HKs(66)(67). The HK dimerization domains have also been proposed as good drug targets for TCSs inhibitors(67).…”