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首页> 外文期刊>Journal of Medicinal Chemistry >Structure-based enhancement of boronic acid-based inhibitors of AmpC beta-lactamase.
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Structure-based enhancement of boronic acid-based inhibitors of AmpC beta-lactamase.

机译：AmpCβ-内酰胺酶基于硼酸的抑制剂的基于结构的增强。

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The expression of beta-lactamases is the most common form of bacterial resistance to beta-lactam antibiotics. To combat these enzymes, agents that inhibit (e.g. clavulanic acid) or evade (e.g. aztreonam) beta-lactamases have been developed. Both the beta-lactamase inhibitors and the beta-lactamase-resistant antibiotics are themselves beta-lactams, and bacteria have responded to these compounds by expressing variant enzymes resistant to inhibition (e.g. IRT-3) or that inactivate the beta-lactamase-resistant antibiotic (e.g. TEM-10). Moreover, these compounds have increased the frequency of bacteria with intrinsically resistant beta-lactamases (e.g. AmpC). In an effort to identify non-beta-lactam-based beta-lactamase inhibitors, we used the crystallographic structure of the m-aminophenylboronic acid-Escherichia coli AmpC beta-lactamase complex to suggest modifications that might enhance the affinity of boronic acid-based inhibitors for class C beta-lactamases. Several types of compounds were modeled into the AmpC binding site, and a total of 37 boronic acids were ultimately tested for beta-lactamase inhibition. The most potent of these compounds, benzo[b]thiophene-2-boronic acid (36), has an affinity for E. coli AmpC of 27 nM. The wide range of functionality represented by these compounds allows for the steric and chemical "mapping" of the AmpC active site in the region of the catalytic Ser64 residue, which may be useful in subsequent inhibitor discovery efforts. Also, the new boronic acid-based inhibitors were found to potentiate the activity of beta-lactam antibiotics, such as amoxicillin and ceftazidime, against bacteria expressing class C beta-lactamases. This suggests that boronic acid-based compounds may serve as leads for the development of therapeutic agents for the treatment of beta-lactam-resistant infections.
机译：β-内酰胺酶的表达是细菌对β-内酰胺抗生素产生抗药性的最常见形式。为了对抗这些酶，已经开发了抑制（例如棒酸）或逃避（例如氨曲南）β-内酰胺酶的试剂。 β-内酰胺酶抑制剂和抗β-内酰胺酶的抗生素本身都是β-内酰胺类，细菌通过表达抗抑制酶（例如IRT-3）或使抗β-内酰胺酶的抗生素失活，对这些化合物产生了反应。 （例如TEM-10）。而且，这些化合物增加了具有内在抗性的β-内酰胺酶（例如AmpC）的细菌的频率。为了确定非基于β-内酰胺的β-内酰胺酶抑制剂，我们使用了间氨基苯硼酸-大肠杆菌AmpCβ-内酰胺酶复合物的晶体结构，以提出可能增强基于硼酸的抑制剂亲和力的修饰用于C类β-内酰胺酶。将几种类型的化合物建模到AmpC结合位点中，最终测试了总共37种硼酸对β-内酰胺酶的抑制作用。这些化合物中最有效的是苯并[b]噻吩-2-硼酸（36），对大肠杆菌AmpC的亲和力为27 nM。这些化合物代表的广泛功能范围允许在催化的Ser64残基区域中AmpC活性位点的空间和化学“映射”，这可能在后续的抑制剂发现工作中有用。而且，发现基于新的基于硼酸的抑制剂增强了β-内酰胺抗生素（例如阿莫西林和头孢他啶）对表达C类β-内酰胺酶的细菌的活性。这表明基于硼酸的化合物可以作为开发用于治疗β-内酰胺耐药性感染的治疗剂的先导。

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