Inhibition of the class C beta-lactamase from Acinetobacter spp.: insights into effective inhibitor design.
Inhibition of the class C beta-lactamase from Acinetobacter spp.: insights into effective inhibitor design.
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抑制c杆菌属的C类β-内酰胺酶：对有效抑制剂设计的见解。
DOI：
10.1021/bi9015988
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发表时间：
2010-01-19
期刊：
影响因子：
2.9
通讯作者：
Bonomo, Robert A.
中科院分区：
文献类型：
--
作者：
Drawz, Sarah M.;Babic, Maja;Bethel, Christopher R.;Taracila, Magda;Distler, Anne M.;Ori, Claudia;Caselli, Emilia;Prati, Fabio;Bonomo, Robert A.
开发针对革兰氏阴性病原体的 C 类头孢菌素酶的 β-内酰胺酶抑制剂的需求是一个紧迫的临床优先事项。为了应对这一挑战，合成了五种硼酸衍生物，包括一种新的头孢哌酮类似物，并针对鲍曼不动杆菌的 C 类头孢菌素酶（不动杆菌衍生头孢菌素酶，ADC）进行了测试。还对市售的碳青霉烯类抗生素进行了分析。在硼酸系列中，具有对应于 β-内酰胺 C3/C4 羧酸酯的间羧基苯基部分的手性头孢噻吩类似物显示出最低的 Ki (11 ± 1 nM)。在抗菌药敏试验中，这种头孢噻肟类似物将携带 blaADC 的大肠杆菌 DH10B 细胞的头孢他啶和头孢噻肟最低抑菌浓度 (MIC) 分别从 16 → 4 μg/ml 和 8 → 1 μg/ml 降低。另一方面，每种碳青霉烯类的 Ki < 20 μM，定时电喷雾电离质谱 (ESI-MS) 证明，与完整的碳青霉烯类和缺乏 C6 羟乙基的碳青霉烯类形成了对应于酰基酶中间体的加合物。为了更好地理解 β-内酰胺酶和抑制剂之间的相互作用，我们构建了 ADC 作为酰基酶的模型：i) 间羧基苯基头孢噻吩类似物； ii)碳青霉烯类亚胺培南和美罗培南。我们的第一个模型表明，这种手性头孢噻吩类似物在 β-内酰胺酶活性位点采用了一种新的构象。此外，添加模拟头孢菌素二氢噻嗪环的取代基可以显着提高与ADC β-内酰胺酶的亲和力。相比之下，ADC：碳青霉烯模型为R2侧基提供了新的作用，并且还表明通过逆醛醇反应消除C6羟乙基会导致酰基酶的显着构象变化。硼酸衍生物和碳青霉烯类的不同机制和结构的经验教训为开发针对这些关键耐药靶标的新型 β-内酰胺酶抑制剂提供了见解。
The need to develop β-lactamase inhibitors against class C cephalosporinases of Gram-negative pathogens represents an urgent clinical priority. To respond to this challenge, five boronic acid derivatives including a new cefoperazone analog were synthesized and tested against the class C cephalosporinase of Acinetobacter baumannii (Acinetobacter-Derived Cephalosporinase, ADC). The commercially available carbapenems antibiotics were also assayed. In the boronic acid series, a chiral cephalothin analog with a meta-carboxyphenyl moiety corresponding to the C3/C4 carboxylate of β-lactams showed the lowest Ki (11 ± 1 nM). In antimicrobial susceptibility tests, this cephalothin analog lowered the ceftazidime and cefotaxime minimum inhibitory concentrations (MICs) of Escherichia coli DH10B cells carrying blaADC from 16 → 4 μg/ml, and 8 → 1 μg/ml, respectively. On the other hand, each carbapenem exhibited a Ki < 20 μM, and timed electrospray ionization mass spectrometry (ESI-MS) demonstrated the formation of adducts corresponding to acyl-enzyme intermediates with both intact carbapenem and carbapenem lacking the C6 hydroxyethyl group. To better understand the interactions between the β-lactamase and the inhibitors, we constructed models of ADC as an acyl-enzyme with: i) the meta-carboxyphenyl cephalothin analog; and ii) the carbapenems imipenem and meropenem. Our first model suggests that this chiral cephalothin analog adopts a novel conformation in the β-lactamase active site. Further, the addition of the substituent mimicking the cephalosporin dihydrothiazine ring may significantly improve affinity for the ADC β-lactamase. In contrast, the ADC: carbapenem models offer a novel role for the R2 side group, and also suggest that elimination of the C6 hydroxyethyl group by retroaldolic reaction leads to a significant conformational change of the acyl-enzyme. Lessons from the diverse mechanisms and structures of the boronic acid derivatives and carbapenems provide insights for the development of new β-lactamase inhibitors against these critical drug resistance targets.
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影响因子：
4.1
作者：
DUBUS, A;WILKIN, JM;FRERE, JM
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FRERE, JM
影响因子：
15
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通讯作者：
Schwede, T