2012年11月14日 訊 /生物谷BIOON/ --近日，刊登在國際雜志Journal of the American Chemical Society (JACS)上的一篇研究報(bào)告中，來自布里斯托大學(xué)和葡萄牙阿威羅大學(xué)的研究者通過研究揭示了一種特定酶的結(jié)構(gòu),，這種酶可以破壞碳青霉烯類抗生素，抑制抗生素發(fā)揮作用,，這種抗生素可以抑制一系列的嚴(yán)重感染,。
細(xì)菌如大腸桿菌可以通過產(chǎn)生特定的碳青霉烯酶來抑制碳青霉烯類抗生素作用的發(fā)揮，從而來破壞其抗菌活性,，繼續(xù)進(jìn)行感染,。碳青霉烯酶是細(xì)菌β內(nèi)酰胺酶的家族成員，β內(nèi)酰胺酶可以破壞青霉素類及其相關(guān)的抗生素，但是為何碳青霉烯酶可以破壞碳青霉烯類抗生素（其它β內(nèi)酰胺酶不能破壞）的分子機(jī)制并不清楚,。
在這項(xiàng)研究中,，研究者使用分子動(dòng)力學(xué)模型，揭示了特定類型的碳青霉烯酶如何結(jié)合至抗生素,，并促進(jìn)其破壞使其效用失效,。研究者使用X射線晶體衍射技術(shù)對(duì)碳青霉烯酶破壞碳青霉烯類抗生素的過程進(jìn)行拍照，隨后進(jìn)行動(dòng)態(tài)模擬實(shí)驗(yàn)?zāi)M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霉烯類抗生素被破壞的詳細(xì)過程，理解此過程可以幫助研究者開發(fā)出新型的藥物來抑制碳青霉烯類抗生素被破壞,。
研究者Spencer說,，結(jié)合實(shí)驗(yàn)技術(shù)和計(jì)算機(jī)技術(shù)我們就可以得到細(xì)菌對(duì)抗生素產(chǎn)生耐藥的一系列起源信息，我們的晶體學(xué)結(jié)果揭示了抗生素被破壞的全部過程,，這就為開發(fā)新型細(xì)菌酶類結(jié)合藥物,，來抑制細(xì)菌耐藥性提供了基礎(chǔ)。
研究者最后表示,，識(shí)別細(xì)菌酶類和抗生素的分子反應(yīng),，對(duì)于我們開發(fā)新型修飾藥物來克服細(xì)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
doi:10.1021/ja304460j
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PMID:
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.
