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首页> 外文期刊>Biochemistry >Structural Basis of Activity against Aztreonam and Extended Spectrum Cephalosporins for Two Carbapenem-Hydrolyzing Class D beta-Lactamases from Acinetobacter baumannii
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Structural Basis of Activity against Aztreonam and Extended Spectrum Cephalosporins for Two Carbapenem-Hydrolyzing Class D beta-Lactamases from Acinetobacter baumannii

机译：来自AztReonam和扩展谱头孢菌素的活动基础，对两种Carbapenem水解D类Dβ-内酰胺酶免受AcinetobacterBaumannii

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The carbapenem-hydrolyzing class D beta-lactamases OXA-23 and OXA-24/40 have emerged worldwide as causative agents for beta-lactam antibiotic resistance in Acinetobacter species. Many Variants of these enzymes have appeared clinically, including OXA-160 and OXA-225, which both contain a P -> S substitution at homologous positions in the OXA-24/40 and OXA-23 background's, respectively. We purified OXA-160 and OXA-225 and used steady-State kinetic analysis to compare the substrate profiles of these variants to their parental enzymes, OXA-24/40 and OXA-23. OXA-160 and OXA-225 possess greatly enhanced hydrolytic activities against aztreonam, ceftazidime, cefotaxime, and ceftriaxone when compared to OXA-24/40 and OXA-23. These enhanced activities are the result of much lower K-m values, suggesting that the P -> S substitution enhances the binding affinity of these drugs. We have determined the structures of the acylated forms of OXA-160 (with ceftazidime and aztreonam) and OXA-225 (ceftazidime). These structures show that the R1 oxyimino side-chain of these drugs occupies a space near the beta 5-beta 6 loop and the omega loop of the enzymes. The P -> S substitution found in OXA-160 and OXA-225 results in a deviation of the beta 5-beta 6 loop, relieving the steric dash with the R1 side-chain carboxypropyl group of aztreonam and ceftazidime. These results reveal worrying trends in the enhancement of substrate spectrum of class beta-lactamases but may also provide a map for Chi-lactam improvement.
机译：将碳烯烃水解D型DETA-乳酰胺氧化β-23和OXA-24/40在全球范围内出现，作为β-内酰胺抗生素抗性的致病剂。这些酶的许多变体已经临床上出现，包括氧气-160和Oxa-225，它们分别在Oxa-24/40和Oxa-23背景中的同源位置含有P - > S取代。我们纯化了Oxa-160和Oxa-225并使用稳态动力学分析，将这些变体的基板轮廓与其父母酶，Oxa-24/40和Oxa-23进行比较。与Oxa-24/40和Oxa-23相比，Oxa-160和Oxa-225对AztReonam，Ceftakidime，Cefotaxime和头孢菌和头孢曲松具有极大的水解活性。这些增强的活性是K-M值更低的结果，表明P - > S取代增强了这些药物的结合亲和力。我们已经确定了酰基化形式的Oxa-160（用Ceftazidime和AztReonam）和Oxa-225（头孢他啶）的结构。这些结构表明，这些药物的R1嗜酸性侧链占据β5-β6环附近的空间和酶的ω环。在氧气-160和Oxa-225中发现的p - > S取代导致β5β6环的偏差，使空间划线与AztReonam和头孢他啶的R1侧链羧基丙基脱落。这些结果揭示了β-内酰胺酶的底物谱的增强的令人担忧的趋势，但也可以提供用于Chi-uncam改善的地图。

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