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Reversibility of Covalent, Broad-Spectrum Serine β-Lactamase Inhibition by the Diazabicyclooctenone ETX2514
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-08-28 00:00:00 , DOI: 10.1021/acsinfecdis.7b00113 Adam B. Shapiro 1 , Ning Gao 2 , Haris Jahić 3 , Nicole M. Carter 1 , April Chen 1 , Alita A. Miller 1
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-08-28 00:00:00 , DOI: 10.1021/acsinfecdis.7b00113 Adam B. Shapiro 1 , Ning Gao 2 , Haris Jahić 3 , Nicole M. Carter 1 , April Chen 1 , Alita A. Miller 1
Affiliation
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ETX2514 is a non-β-lactam serine β-lactamase inhibitor in clinical development that has greater potency and broader spectrum of β-lactamase inhibition than the related diazabicyclooctanone avibactam. Despite opening of its cyclic urea ring upon acylation, avibactam can recyclize and dissociate intact from certain β-lactamases. We investigated reversibility of ETX2514 acylation of 10 serine β-lactamases representing Ambler classes A, C, and D. Dissociation rate constants varied widely between enzymes and were lowest for class D. For most enzymes, the covalent adduct mass was that of ETX2514 (277 Da). OXA-10 was acylated with 277 and 197 Da adducts, consistent with loss of the sulfate moiety. KPC-2 showed only the 197 Da adduct. ETX2514 recyclized and dissociated intact from AmpC, CTX-M-15, P99, SHV-5 and TEM-1 but not from KPC-2, OXA-10, OXA-23, OXA-24, or OXA-48. Inactivation partition ratios were 1 for all enzymes except KPC-2, for which it increased to 3.0 after 2 h. This result and mass spectrometry showed that KPC-2 very slowly degraded ETX2514. Nevertheless, ETX2514 restored β-lactam activity to equal potency against isogenic Pseudomonas aeruginosa strains each overexpressing one of the 10 β-lactamases.
中文翻译：
二氮杂双环辛烯酮ETX2514抑制共价，广谱丝氨酸β-内酰胺酶的可逆性
ETX2514是临床开发中的一种非β-内酰胺丝氨酸β-内酰胺酶抑制剂，与相关的二氮杂双环辛酮avibactam相比，具有更大的效力和更广的β-内酰胺酶抑制作用。尽管在酰化作用下会打开其环状脲环，但avibactam仍能从某些β-内酰胺酶中循环并解离完整。我们研究了代表Ambler A，C和D类的10种丝氨酸β-内酰胺酶ETX2514酰化的可逆性。解离速率常数在酶之间差异很大，对于D类最低。对于大多数酶，共价加合物的质量是ETX2514（277 ）。OXA-10被277和197 Da加合物酰化，这与硫酸盐部分的丢失相一致。KPC-2仅显示197 Da加合物。ETX2514完整地从AmpC，CTX-M-15，P99，SHV-5和TEM-1回收并解离，但未从KPC-2，OXA-10，OXA-23，OXA-24或OXA-48。除KPC-2外，所有酶的灭活分配比均为1，2小时后，其增加至3.0。该结果和质谱表明，KPC-2非常缓慢地降解了ETX2514。尽管如此，ETX2514仍将β-内酰胺活性恢复至与等基因相同的效力铜绿假单胞菌菌株各自过表达10种β-内酰胺酶之一。
更新日期：2017-08-28
中文翻译：
二氮杂双环辛烯酮ETX2514抑制共价，广谱丝氨酸β-内酰胺酶的可逆性
ETX2514是临床开发中的一种非β-内酰胺丝氨酸β-内酰胺酶抑制剂，与相关的二氮杂双环辛酮avibactam相比，具有更大的效力和更广的β-内酰胺酶抑制作用。尽管在酰化作用下会打开其环状脲环，但avibactam仍能从某些β-内酰胺酶中循环并解离完整。我们研究了代表Ambler A，C和D类的10种丝氨酸β-内酰胺酶ETX2514酰化的可逆性。解离速率常数在酶之间差异很大，对于D类最低。对于大多数酶，共价加合物的质量是ETX2514（277 ）。OXA-10被277和197 Da加合物酰化，这与硫酸盐部分的丢失相一致。KPC-2仅显示197 Da加合物。ETX2514完整地从AmpC，CTX-M-15，P99，SHV-5和TEM-1回收并解离，但未从KPC-2，OXA-10，OXA-23，OXA-24或OXA-48。除KPC-2外，所有酶的灭活分配比均为1，2小时后，其增加至3.0。该结果和质谱表明，KPC-2非常缓慢地降解了ETX2514。尽管如此，ETX2514仍将β-内酰胺活性恢复至与等基因相同的效力铜绿假单胞菌菌株各自过表达10种β-内酰胺酶之一。
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