Unique Diacidic Fragments Inhibit the OXA-48 Carbapenemase and Enhance the Killing of Escherichia coli Producing OXA-48.
Unique Diacidic Fragments Inhibit the OXA-48 Carbapenemase and Enhance the Killing of Escherichia coli Producing OXA-48.
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DOI：
10.1021/acsinfecdis.1c00501
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发表时间：
2021-12-10
影响因子：
5.3
通讯作者：
Palzkill, Timothy
中科院分区：
文献类型：
--
作者：
Taylor, Doris Mia;Anglin, Justin;Hu, Liya;Wang, Lingfei;Sankaran, Banumathi;Wang, Jin;Matzuk, Martin M.;Prasad, B. V. Venkataram;Palzkill, Timothy
关键词：
尽管 β-内酰胺酶抑制剂的开发取得了进展，但 D 类碳青霉烯酶 OXA-48 的选择仍然有限。 OXA-48 是碳青霉烯类耐药肠杆菌科细菌感染中最常见的碳青霉烯酶之一，并且对大多数可用的 β-内酰胺酶抑制剂不敏感。在这里，我们针对 OXA-48 筛选了各种低分子量化合物（片段），以确定用于抑制剂开发的功能支架。研究发现，几种联苯、萘、芴、蒽醌和偶氮苯类化合物尽管尺寸较小，但仍能以低微摩尔效力抑制 OXA-48。 OXA-48 与其中几种化合物的共晶结构揭示了与羧酸盐结合袋、Arg214 和 β-内酰胺酶的各种疏水残基的关键相互作用，可在未来的抑制剂开发中利用。许多低微摩尔效力的抑制剂，在不同的支架上，与氨苄西林协同作用，杀死表达 OXA-48 的大肠杆菌，尽管各自抑制剂的浓度很高。此外，几种化合物对鲍曼不动杆菌中普遍存在的 OXA-24 和 OXA-58 D 类碳青霉烯酶表现出微摩尔效力。这项工作提供了各种化学支架的基础信息，可以指导有效的 OXA-48 抑制剂的设计，这些抑制剂保持对其他主要 D 类碳青霉烯酶的功效和效力。该图显示了针对 OXA-48 碳青霉烯酶测试的化合物的各种支架以及 OXA-48 与芴基抑制剂的共晶结构。这项工作揭示了各种基于单酸和二酸片段的化合物如何结合和抑制 OXA-48，以及它们在体外对大肠杆菌的功效，尽管它们的尺寸很小。
Despite advances in β-lactamase inhibitor development, limited options exist for the class D carbapenemase known as OXA-48. OXA-48 is one of the most prevalent carbapenemases in carbapenem-resistant Enterobacteriaceae infections and is not susceptible to most available β-lactamase inhibitors. Here, we screened various low molecular weight compounds (fragments) against OXA-48 to identify functional scaffolds for inhibitor development. Several biphenyl-, naphthalene-, fluorene-, anthraquinone-, and azobenzene-based compounds were found to inhibit OXA-48 with low micromolar potency despite their small size. Co-crystal structures of OXA-48 with several of these compounds revealed key interactions with the carboxylate binding pocket, Arg214, and various hydrophobic residues of β-lactamase that can be exploited in future inhibitor development. A number of the low micromolar potency inhibitors, across different scaffolds, synergize with ampicillin to kill E. coli expressing OXA-48, albeit at high concentrations of the respective inhibitors. Additionally, several compounds demonstrated micromolar potency towards the OXA-24 and OXA-58 class D carbapenemases that are prevalent in Acinetobacter baumannii. This work provides foundational information on a variety of chemical scaffolds that can guide the design of effective OXA-48 inhibitors that maintain efficacy as well as potency towards other major class D carbapenemases. The graphic shows the variety of scaffolds of the compounds tested against the OXA-48 carbapenemase and a co-crystal structure of OXA-48 with a fluorene-based inhibitor. The work reveals how various monoacidic and diacidic fragment-based compounds bind and inhibit OXA-48 as well as their efficacy against E. coli in vitro despite their small size.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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DOI：
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发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
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影响因子：
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