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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Modified Penicillin Molecule with Carbapenem- Like Stereochemistry Specifically Inhibits Class C beta-Lactamases
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Modified Penicillin Molecule with Carbapenem- Like Stereochemistry Specifically Inhibits Class C beta-Lactamases

机译：用CarbapeNem的改性青霉素分子，类似于立体化学特异性抑制C类β-内酰胺酶

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摘要

Bacterial beta-actamases readily inactivate most penicillins and cephalosporins by hydrolyzing and "opening" their signature beta-lactam ring. In contrast, carbapenems resist hydrolysis by many serine-based class A, C, and D beta-lactamases due to their unique stereochemical features. To improve the resistance profile of penicillins, we synthesized a modified penicillin molecule, MPC-1, by "grafting" carbapenem-like stereochemistry onto the penicillin core. Chemical modifications include the trans conformation of hydrogen atoms at C-5 and C-6 instead of cis, and a 6-alpha hydroxyethyl moiety to replace the original 6-beta aminoacyl group. MPC-1 selectively inhibits class C beta-lactamases, such as P99, by forming a nonhydrolyzable acyl adduct, and its inhibitory potency is similar to 2 to 5 times higher than that for clinically used beta-lactamase inhibitors clavulanate and sulbactam. The crystal structure of MPC-1 forming the acyl adduct with P99 reveals a novel binding mode for MPC-1 that resembles carbapenem bound in the active site of class A beta-lactamases. Furthermore, in this novel binding mode, the carboxyl group of MPC-1 blocks the deacylation reaction by occluding the critical catalytic water molecule and renders the acyl adduct nonhydrolyzable. Our results suggest that by incorporating carbapenem-like stereochemistry, the current collection of over 100 penicillins and cephalosporins can be modified into candidate compounds for development of novel beta-lactamase inhibitors.
机译：细菌β-actamase通过水解和“开启”它们的签名β-内酰胺环来易于活跃大多数青霉素和头孢菌素。相比之下，由于其独特的立体化特征，CarbapeNems通过许多丝氨酸类A，C和Dβ-内酰胺酶抵抗水解。为了改善青霉素的抗性曲线，通过将改性的青霉素分子，MPC-1相合并，通过将“嫁接”碳烯烯形状的立体化学在青霉素核心上。化学修饰包括C-5和C-6代替CIS的氢原子的反式构象，以及6-α羟乙基部分以替代原始的6-β氨基酰基。 MPC-1选择性地抑制C类β-内酰胺酶，例如P99，通过形成不可脱水的酰基加合物，其抑制效力与临床使用的β-内酰胺酶抑制剂克拉维酸酯和苏术酸克拉氨酸和抑制剂高2至5倍。用P99形成酰基加合物的MPC-1的晶体结构显示了MPC-1的新型结合模式，其类似于β-内酰胺酶的活性位点中的CarbapeNem。此外，在这种新的结合模式中，MPC-1的羧基通过堵塞临界催化水分子阻断脱酰化反应，使酰基加合物不可溶解。我们的研究结果表明，通过纳入CarbapeNem样的立体化学，可以将100多个青霉素和头孢菌素的收集成候选化合物，用于开发新型β-内酰胺酶抑制剂。

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