Succinic acids as potent inhibitors of plasmid-borne IMP-1 metallo-β-lactamase
Succinic acids as potent inhibitors of plasmid-borne IMP-1 metallo-β-lactamase
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DOI：
10.1074/jbc.m104742200
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发表时间：
2001-08-24
影响因子：
4.8
通讯作者：
Gao, YD
中科院分区：
文献类型：
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作者：
Toney, JH;Hammond, GG;Gao, YD
IMP-1金属-β-内酰胺酶（B类）是一种质粒携带的锌金属酶，可有效水解β-内酰胺抗生素，包括碳青霉烯类，使其无效。由于IMP-1已在几种临床上重要的碳青霉烯类耐药病原体中发现，因此需要这种酶的抑制剂，其可以保护广谱抗生素如亚胺培南免于水解，从而延长其效用。我们已经鉴定了一系列2，3-（S，S）-二取代琥珀酸，它们是IMP-1的有效抑制剂。琥珀酸抑制剂复合物与IMP-1的高分辨率晶体结构和分子建模的测定允许了解这些抑制剂的效力，立体化学和结构-活性关系。
IMP-1 metallo-beta -lactamase (class B) is a plasmid-borne zinc metalloenzyme that efficiently hydrolyzes beta -lactam antibiotics, including carbapenems, rendering them ineffective. Because IMP-1 has been found in several clinically important carbapenem-resistant pathogens, there is a need for inhibitors of this enzyme that could protect broad spectrum antibiotics such as imipenem from hydrolysis and thus extend their utility. We have identified a series of 2,3-(S,S)-disubstituted succinic acids that are potent inhibitors of IMP-1. Determination of high resolution crystal structures and molecular modeling of succinic acid inhibitor complexes with IMP-1 has allowed an understanding of the potency, stereochemistry, and structure-activity relationships of these inhibitors.