Department of Bioscience, Graduate School of Agriculture, Kinki University, Nara, Japan.
J Antibiot (Tokyo). 2010 Mar;63(3):127-34. doi: 10.1038/ja.2010.4. Epub 2010 Jan 29.
The WalK/WalR (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/WalR 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 WalR inhibitors and identify two novel inhibitors targeting the WalR response regulator (RR): walrycin A (4-methoxy-1-naphthol) and walrycin B (1,6-dimethyl-3-[4-(trifluoromethyl)phenyl]pyrimido[5,4-e][1,2,4]triazine-5,7-dione). Addition of these compounds simultaneously affects the expression of WalR regulon genes, leading to phenotypes consistent with those of cells starved for the WalK/WalR 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 WalR in B. subtilis and S. aureus.
WalK/WalR（YycG/YycF）双组分系统对细胞活力至关重要，高度保守且特异性地存在于低 GC 百分比的革兰氏阳性菌中，使其成为新型抗菌化合物的有吸引力的靶标。最近的工作表明，WalK/WalR 作为主调控系统，在控制和协调枯草芽孢杆菌和金黄色葡萄球菌的细胞壁代谢与细胞分裂方面发挥作用。在本文中，我们开发了一种针对 WalR 抑制剂的高通量筛选系统，并鉴定出两种针对 WalR 应答调节剂（RR）的新型抑制剂：walrycin A（4-甲氧基-1-萘酚）和 walrycin B（1,6-二甲基-3-[4-（三氟甲基）苯基]嘧啶并[5,4-e][1,2,4]三嗪-5,7-二酮）。这些化合物的添加同时影响 WalR 调控基因的表达，导致与 WalK/WalR 系统饥饿的细胞表型一致，并具有杀菌作用。在这些条件下，枯草芽孢杆菌细胞形成非常长的无隔膜丝，金黄色葡萄球菌细胞形成大的聚集体。这些结果表明，walrycins A 和 B 是枯草芽孢杆菌和金黄色葡萄球菌中针对 WalR 的首批抗菌剂。
