2012年11月14日 訊 /生物谷BIOON/ --近日，刊登在國際雜誌Journal of the American Chemical Society (JACS)上的一篇研究報告中，來自布裡斯託大學和葡萄牙阿威羅大學的研究者通過研究揭示了一種特定酶的結構，這種酶可以破壞碳青黴烯類抗生素，抑制抗生素髮揮作用，這種抗生素可以抑制一系列的嚴重感染。
細菌如大腸桿菌可以通過產生特定的碳青黴烯酶來抑制碳青黴烯類抗生素作用的發揮，從而來破壞其抗菌活性，繼續進行感染。碳青黴烯酶是細菌β內醯胺酶的家族成員，β內醯胺酶可以破壞青黴素類及其相關的抗生素，但是為何碳青黴烯酶可以破壞碳青黴烯類抗生素（其它β內醯胺酶不能破壞）的分子機制並不清楚。
在這項研究中，研究者使用分子動力學模型，揭示了特定類型的碳青黴烯酶如何結合至抗生素，並促進其破壞使其效用失效。研究者使用X射線晶體衍射技術對碳青黴烯酶破壞碳青黴烯類抗生素的過程進行拍照，隨後進行動態模擬實驗模擬抗生素被破壞的過程。
在模擬過程中，研究者就可以看到碳青黴烯類抗生素被破壞的詳細過程，理解此過程可以幫助研究者開發出新型的藥物來抑制碳青黴烯類抗生素被破壞。
研究者Spencer說，結合實驗技術和計算機技術我們就可以得到細菌對抗生素產生耐藥的一系列起源信息，我們的晶體學結果揭示了抗生素被破壞的全部過程，這就為開發新型細菌酶類結合藥物，來抑制細菌耐藥性提供了基礎。
研究者最後表示，識別細菌酶類和抗生素的分子反應，對於我們開發新型修飾藥物來克服細菌的抗生素耐藥性帶來了很大幫助。（生物谷Bioon.com）
編譯自：Understanding Antibiotic Resistance Using Crystallography and Computation
The Basis for Carbapenem Hydrolysis by Class A β-Lactamases: A Combined Investigation using Crystallography and Simulations
Fátima Fonseca *†‡, Ewa I. Chudyk §, Marc W. van der Kamp §, António Correia ‡, Adrian J. Mulholland *§, and James Spencer *†
Carbapenems are the most potent β-lactam antibiotics and key drugs for treating infections by Gram-negative bacteria. In such organisms, β-lactam resistance arises principally from β-lactamase production. Although carbapenems escape the activity of most β-lactamases, due in the class A enzymes to slow deacylation of the covalent acylenzyme intermediate, carbapenem-hydrolyzing class A β-lactamases are now disseminating in clinically relevant bacteria. The reasons why carbapenems are substrates for these enzymes, but inhibit other class A β-lactamases, remain to be fully established. Here, we present crystal structures of the class A carbapenemase SFC-1 from Serratia fonticola and of complexes of its Ser70 Ala (Michaelis) and Glu166 Ala (acylenzyme) mutants with the carbapenem meropenem. These are the first crystal structures of carbapenem complexes of a class A carbapenemase. Our data reveal that, in the SFC-1 acylenzyme complex, the meropenem 6α-1R-hydroxyethyl group interacts with Asn132, but not with the deacylating water molecule. Molecular dynamics simulations indicate that this mode of binding occurs in both the Michaelis and acylenzyme complexes of wild-type SFC-1. In carbapenem-inhibited class A β-lactamases, it is proposed that the deacylating water molecule is deactivated by interaction with the carbapenem 6α-1R-hydroxyethyl substituent. Structural comparisons with such enzymes suggest that in SFC-1 subtle repositioning of key residues (Ser70, Ser130, Asn132 and Asn170) enlarges the active site, permitting rotation of the carbapenem 6α-1R-hydroxyethyl group and abolishing this contact. Our data show that SFC-1, and by implication other such carbapenem-hydrolyzing enzymes, uses Asn132 to orient bound carbapenems for efficient deacylation and prevent their interaction with the deacylating water molecule.