Toney J H, Hammond G G, Fitzgerald P M, Sharma N, Balkovec J M, Rouen G P, Olson S H, Hammond M L, Greenlee M L, Gao Y D
Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
J Biol Chem. 2001 Aug 24;276(34):31913-8. doi: 10.1074/jbc.M104742200. Epub 2001 Jun 4.
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.
IMP-1金属β-内酰胺酶(B类)是一种由质粒携带的锌金属酶,它能有效水解包括碳青霉烯类在内的β-内酰胺抗生素,使其失效。由于在几种临床上重要的耐碳青霉烯病原体中都发现了IMP-1,因此需要这种酶的抑制剂,以保护亚胺培南等广谱抗生素不被水解,从而扩大其应用范围。我们已经鉴定出一系列2,3-(S,S)-二取代琥珀酸,它们是IMP-1的强效抑制剂。通过测定琥珀酸抑制剂与IMP-1复合物的高分辨率晶体结构和分子建模,得以了解这些抑制剂的效力、立体化学和构效关系。