Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase
Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase
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DOI：
10.1021/acs.jmedchem.9b00625
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发表时间：
2019-08-22
影响因子：
7.3
通讯作者：
Cohen, Frederick
中科院分区：
文献类型：
--
作者：
Andrews, Logan D.;Kane, Timothy R.;Cohen, Frederick
新抗生素发现的一个主要挑战是预测使小分子能够渗透革兰氏阴性细菌膜的物理化学性质。我们已经从以前的工作中应用物理化学的经验教训，重新设计和提高生物素羧化酶（BC）的吡啶并嘧啶抑制剂的抗菌效力高达64倍和16倍对大肠杆菌和铜绿假单胞菌，分别。在存在外膜透化剂或流出受损菌株的情况下进行的抗菌和酶效力评估表明，许多重新设计的BC抑制剂的渗透和流出特性可以在不同程度上得到改善。铜绿假单胞菌对改进的吡啶并嘧啶抑制剂的自发耐药发生频率非常低，在10（-8）和10（-9）之间。然而，与亲本菌株相比，耐药分离株具有惊人的高最小抑制浓度变化（16至>128倍）。耐药分离株的全基因组测序显示，BC靶点突变或外排泵过表达均可导致高水平耐药的发展。
A major challenge for new antibiotic discovery is predicting the physicochemical properties that enable small molecules to permeate Gram-negative bacterial membranes. We have applied physicochemical lessons from previous work to redesign and improve the antibacterial potency of pyridopyrimidine inhibitors of biotin carboxylase (BC) by up to 64-fold and 16-fold against Escherichia coli and Pseudomonas aeruginosa, respectively. Antibacterial and enzyme potency assessments in the presence of an outer membrane-permeabilizing agent or in efflux-compromised strains indicate that penetration and efflux properties of many redesigned BC inhibitors could be improved to various extents. Spontaneous resistance to the improved pyridopyrimidine inhibitors in P. aeruginosa occurs at very low frequencies between 10(-8) and 10(-9). However, resistant isolates had alarmingly high minimum inhibitory concentration shifts (16- to >128-fold) compared to the parent strain. Whole-genome sequencing of resistant isolates revealed that either BC target mutations or efflux pump overexpression can lead to the development of high-level resistance.