Novel Terminal Bipheny-Based Diapophytoene Desaturases (CrtN) Inhibitors as Anti-MRSA/VISR/LRSA Agents with Reduced hERG Activity
Novel Terminal Bipheny-Based Diapophytoene Desaturases (CrtN) Inhibitors as Anti-MRSA/VISR/LRSA Agents with Reduced hERG Activity
复制标题
新型末端联苯基二坡植物烯去饱和酶 (CrtN) 抑制剂作为抗 MRSA/VISR/LRSA 药物，可降低 hERG 活性
DOI：
10.1021/acs.jmedchem.7b01300
复制
发表时间：
2018-01-11
影响因子：
7.3
通讯作者：
Li, Jian
中科院分区：
文献类型：
--
作者：
Li, Baoli;Ni, Shuaishuai;Li, Jian
CrtN已被鉴定为用于治疗有色金黄色葡萄球菌感染的有吸引力的和可药用的靶标。针对CrtN抑制剂1的缺陷，合成了100多种新化合物。类似物23 a和23 b显示出显著的抗色素S.金黄色葡萄球菌纽曼和13 MRSA菌株（IC 50 = 0.02-10.5 nM），沿着较低的hERG抑制（IC 50> 30 μ M，与1相比类似于10倍降低）。此外，证实23 a和23 b在正常处理的小鼠模型中降低肾脏和心脏中的葡萄球菌负荷比预处理更深，甚至与万古霉素和利奈唑胺相当。值得注意的是，23 a可以强烈地阻断这九种多重耐药MRSA菌株的色素生物合成，包括对LRSA菌株和VISA菌株的优异体内活性，并且所有这些都证明23 a作为治疗药物具有对抗难治性MRSA、VISA和LRSA问题的巨大潜力。
CrtN has been identified as an attractive and druggable target for treating pigmented Staphylococcus aureus infections. More than 100 new compounds were synthesized, which target the overwhelming the defects of the CrtN inhibitor 1. Analogues 23a and 23b demonstrated a significant activity against pigmented S. aureus Newman and 13 MRSA strains (IC50 = 0.02-10.5 nM), along with lower hERG inhibition (IC50 > 30 mu M, similar to 10-fold decrease in comparison with 1). Furthermore, 23a and 23b were confirmed to reduce the staphylococcal load in the kidney and heart in a mouse model with normal treatment deeper than pretreatment ones, comparable even with vancomycin and linezolid. Remarkably, 23a could strongly block the pigment biosynthesis of these nine multidrug-resistant MRSA strains, including excellent activity against LRSA strains and VISA strains in vivo, and all of which demonstrated that 23a has a huge potential against intractable MRSA, VISA, and LRSA issues as a therapeutic drug.