Novel antibacterial compounds specifically targeting the essential WalR response regulator

The WalK/WaIR (YycG/YycF) two-component system, which is essential for cell viability, is highly conserved and specific to low-GC percentage of Gram-positive bacteria, making it an attractive target for novel antimicrobial compounds. Recent work has shown that WalK/WaIR exerts an effect as a master regulatory system in controlling and coordinating cell wall metabolism with cell division in Bacillus subtilis and Staphylococcus aureus. In this paper, we develop a high-throughput screening system for WaIR inhibitors and identify two novel inhibitors targeting the WaIR response regulator (RR): walrycin A (4-methoxy-1-naphthol) and walrycin B (1,6-dimethy1-3[4-(trifluoromethyl)phenyl]pyrimido[5,4-e][ 1,2,4]triazine-5,7-dione). Addition of these compounds simultaneously affects the expression of WaIR regulon genes, leading to phenotypes consistent with those of cells starved for the WalK/WaIR system and having a bactericidal effect. B. subtilis cells form extremely long aseptate filaments and S. aureus cells form large aggregates under these conditions. These results show that walrycins A and B are the first antibacterial agents targeting WaIR in B. subtilis and S. aureus. The Journal of Antibiotics (2010) 63, 127-134; doi:10.1038/ja.2010.4; published online 29 January 2010