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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Nacubactam Enhances Meropenem Activity against Carbapenem-Resistant Klebsiella pneumoniae Producing KPC
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Nacubactam Enhances Meropenem Activity against Carbapenem-Resistant Klebsiella pneumoniae Producing KPC

机译：NaCucActam增强了对抵抗Carbapenem抗性Klebsiella肺炎的梅洛宁活动，产生KPC

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Carbapenem-resistant Enterobacteriaceae (CRE) are resistant to most antibiotics, making CRE infections extremely difficult to treat with available agents. Klebsiella pneurnoniae carbapenemases (KPC-2 and KPC-3) are predominant carbapenemases in CRE in the United States. Nacubactam is a bridged diazabicyclooctane (DBO) beta-lactamase inhibitor that inactivates class A and C beta-lactamases and exhibits intrinsic antibiotic and beta-lactam "enhancer" activity against Enterobacteriaceae. In this study, we examined a collection of meropenem-resistant K pneumoniae isolates carrying bla(KPC-2) or bla(KPC-3); meropenem-nacubactam restored susceptibility. Upon testing isogenic Escherichia coli strains producing KPC-2 variants with single residue substitutions at important Ambler class A positions (K73, S130, R164, E166, N170, D179, K234, E276, etc.), the K234R variant increased the meropenemnacubactam MIC compared to that for the strain producing KPC-2, without increasing the meropenem MIC. Correspondingly, nacubactam inhibited KPC-2 (apparent K-i [K-iapp] = 31 +/- 3 mu M) more efficiently than the K234R variant (K-i app = 270 +/-27 mu M) and displayed a faster acylation rate (k(2)/K, which was 5,815 +/- 582 M-1 s(-1) for KPC-2 versus 247 +/- 25 M-1 s(-1) for the K234R variant. Unlike avibactam, timed mass spectrometry revealed an intact sulfate on nacubactam and a novel peak (+337 Da) with the K234R variant. Molecular modeling of the K234R variant showed significant catalytic residue (i.e., 570, K73, and 5130) rearrangements that likely interfere with nacubactam binding and acylation. Nacubactam's aminoethoxy tail formed unproductive interactions with the K234R variant's active site. Molecular modeling and docking observations were consistent with the results of biochemical analyses. Overall, the meropenem-nacubactam combination is effective against carbapenem-resistant K. pneumoniae. Moreover, our data suggest that p-lactamase inhibition by nacubactam proceeds through an alternative mechanism compared to that for avibactam.
机译：Carbapenem抗性的肠杆菌（CRE）对大多数抗生素具有抗性，使CRE感染极难治疗可用剂。 Klebsiella fneurnoniae carbapenemase（kpc-2和kpc-3）是美国克雷的主要碳蔗糖酶。 NaCucActam是一种桥接的二氮杂双环辛烷（DBO）β-内酰胺酶抑制剂，其灭活A和Cβ-内酰胺酶，并展示针对肠杆菌的内在抗生素和β-内酰胺“增强剂”活性。在这项研究中，我们研究了携带BLA（KPC-2）或BLA（KPC-3）的售价抗氟芬氏抗肺炎肺炎的集合;梅洛涅姆 - Nacubactam恢复了易感性。在测试中源性大肠杆菌菌株中，在重要的Ambler A类中产生具有单残基取代的KPC-2变体的菌株（K73，S130，R164，E166，N170，D179，K234，E276等），K234R变异比较了MEROPENACHACAMACTAM MIC为了产生KPC-2的菌株，而不增加梅洛涅克MIC。相应地，NaCucActam抑制KPC-2（表观Ki [K-IAPP] = 31 +/-3μm）比K234R变体（Ki App = 270 +/-27μm）更有效地效率，并显示出更快的酰化速率（k （2）/ k为KPC-2的5,815 +/- 582 m-1 s（-1），适用于K234R变体的247 +/- 25 m-1 s（-1）。与Avibactam，定时质谱不同用K234R变体揭示了在NaCACTAM和新型峰（+337Da）上完整的硫酸盐。K234R变体的分子建模显示出可能干扰NaCachactam结合和酰化的显着催化残余物（即570，K73和5130）重排。 NaCucActam的氨基乙氧基尾巴与K234R变体的活性位点形成了不生产的相互作用。分子建模和对接观察与生化分析结果一致。总体而言，梅洛宁-Nacubactam组合对肺癌肺癌有效。此外，我们的数据表明我们的数据表明NaCACACAM的p-酰胺酶抑制通过A与Avibactam相比，n替代机制。

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