2012年8月12日 訊 /生物谷BIOON/ --刊登在近日的國際雜志Antimicrobial Agents and Chemotherapy上的一篇研究報告中,，來自挪威特羅姆瑟大學等處的研究者揭示了綠膿桿菌可移動的金屬β內(nèi)酰胺酶的晶體結(jié)構(gòu),，這就為新型抗生素療法提供了一些思路。相關(guān)研究成果標題為“Crystal Structure of the Mobile Metallo-β-Lactamase AIM-1 from Pseudomonas aeruginosa： Insights into Antibiotic Binding and the Role of Gln157”,。
近些年來,，由于人們抗生素的濫用，細菌的耐藥性不斷增強,，其中綠膿桿菌就是一種對很多抗生素都具有極強耐藥性的菌株,，其是院內(nèi)常見的幾大感染性菌株之一，可引發(fā)患者肺炎,，嚴重可導致其發(fā)展為肺纖維囊腫甚至肺癌,。開發(fā)治療綠膿桿菌感染的新型療法對于臨床醫(yī)生和科學家們都迫在眉睫。
綠膿桿菌的金屬β內(nèi)酰胺酶（MBL）類基因可以介導細菌對β內(nèi)酰胺類抗生素產(chǎn)生抗性,，而且其通過快速可移動的遺傳元件來在細菌體內(nèi)發(fā)揮耐藥的作用,。MBLs包括三個不同的亞族，B1,、B2和B3,，然而攜帶可移動MBLs的遺傳元件僅僅限于B1亞族,。B3 MBLs亞族是一個多分化的亞族,，主要負責染色體編碼酶類。
綠膿桿菌的AIM-1（Adelaide Imipenmase 1）是第一個發(fā)現(xiàn)的B3家族的MBL,，在文章中,，研究者揭示了AIM-1的晶體結(jié)構(gòu)，并且使用硅對接,、量子力學和分子力學的方法進行計算,，加上定點誘變的方法來研究AIM-1和β內(nèi)酰胺類抗生的互作機制。AIM-1采取MBLs典型的αβ/βα三倍折疊股方式,，和其它B3酶類不一樣,，其它B3酶類使用二硫鍵形成的方式,。研究結(jié)果表明，AIM-1的底物結(jié)合部位相比其它B3 MBLs非常狹窄而且嚴格,，這也解釋了其高度的催化活性,。
研究者發(fā)現(xiàn)，緊鄰AIM-1的Gln157鋅中心或許可以成為藥物的結(jié)合靶點,，然而AIM-1殘基Asn和Ala的移去會影響到其活性,，這也就揭示了這兩個殘基的重要性。最后研究者Samuelsen表示,，我們的研究揭示了AIM-1是B3 MBL的一個亞類,，其具有新型的晶體結(jié)構(gòu)和機械特性。（生物谷Bioon.com）
doi:10.1128/AAC.00448-12
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PMID:
Crystal Structure of the Mobile Metallo-β-Lactamase AIM-1 from Pseudomonas aeruginosa: Insights into Antibiotic Binding and the Role of Gln157
Hanna-Kirsti S. Leirosa, Pardha S. Borrab, Bjørn Olav Brandsdala,c, Kine Susann Waade Edvardsena, James Spencerd, Timothy R. Walshe and Ørjan Samuelsenf
Metallo-β-lactamase (MBL) genes confer resistance to virtually all β-lactam antibiotics and are rapidly disseminated by mobile genetic elements in Gram-negative bacteria. MBLs belong to three different subgroups, B1, B2, and B3, with the mobile MBLs largely confined to subgroup B1. The B3 MBLs are a divergent subgroup of predominantly chromosomally encoded enzymes. AIM-1 (Adelaide IMipenmase 1) from Pseudomonas aeruginosa was the first B3 MBL to be identified on a readily mobile genetic element. Here we present the crystal structure of AIM-1 and use in silico docking and quantum mechanics and molecular mechanics (QM/MM) calculations, together with site-directed mutagenesis, to investigate its interaction with β-lactams. AIM-1 adopts the characteristic αβ/βα sandwich fold of MBLs but differs from other B3 enzymes in the conformation of an active site loop (residues 156 to 162) which is involved both in disulfide bond formation and, we suggest, interaction with substrates. The structure, together with docking and QM/MM calculations, indicates that the AIM-1 substrate binding site is narrower and more restricted than those of other B3 MBLs, possibly explaining its higher catalytic efficiency. The location of Gln157 adjacent to the AIM-1 zinc center suggests a role in drug binding that is supported by our in silico studies. However, replacement of this residue by either Asn or Ala resulted in only modest reductions in AIM-1 activity against the majority of β-lactam substrates, indicating that this function is nonessential. Our study reveals AIM-1 to be a subclass B3 MBL with novel structural and mechanistic features.
