Structure–Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a promising drug
target in Gram-negative bacteria. Previously, we described a correlation
between the residence time of inhibitors on Pseudomonas
aeruginosa LpxC (paLpxC) and the
post-antibiotic effect (PAE) caused by the inhibitors on the growth
of P. aeruginosa. Given that drugs
with prolonged activity following compound removal may have advantages
in dosing regimens, we have explored the structure–kinetic
relationship for paLpxC inhibition by analogues of
the pyridone methylsulfone PF5081090 (1)
originally developed by Pfizer. Several analogues have longer residence
times on paLpxC than 1 (41 min) including PT913, which has a residence time of 124 min. PT913 also has a PAE of 4 h, extending the original correlation observed
between residence time and PAE. Collectively, the studies provide
a platform for the rational modulation of paLpxC
inhibitor residence time and the potential development of antibacterial
agents that cause prolonged suppression of bacterial growth.

UDP-3-O-(R-3-羟基肉豆蔻酰)-N-乙酰葡糖胺脱乙酰酶（LpxC）是革兰氏阴性菌中极具潜力的药物靶点。此前本团队曾报道，铜绿假单胞菌LpxC（paLpxC）结合抑制剂的滞留时间，与该抑制剂对铜绿假单胞菌生长造成的抗生素后效应（post-antibiotic effect, PAE）之间存在相关性。鉴于化合物清除后仍能维持持久活性的药物在给药方案中具备显著优势，我们针对辉瑞（Pfizer）最初开发的吡啶酮甲基砜类化合物PF5081090（1）的类似物，探究了其抑制paLpxC的结构-动力学关系。多款类似物对paLpxC的滞留时间长于化合物1的41分钟，其中PT913的滞留时间可达124分钟。PT913同时展现出4小时的抗生素后效应，进一步拓展了此前观察到的滞留时间与PAE之间的相关性。综上，本研究为合理调控paLpxC抑制剂的滞留时间提供了研究平台，也为开发可长期抑制细菌生长的抗菌药物提供了潜在可能。