ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii
ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii
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DOI：
10.1038/nmicrobiol.2017.104
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发表时间：
2017-09-01
影响因子：
28.3
通讯作者：
Miller, Alita A.
中科院分区：
文献类型：
--
作者：
Durand-Reville, Thomas F.;Guler, Satenig;Miller, Alita A.
多重耐药（MDR）细菌感染是对公共卫生的严重威胁。最令人担忧的耐药性趋势之一是β-内酰胺酶的数量和多样性迅速增加，β-内酰胺酶是一类几十年来一直是治疗支柱的抗生素。尽管几种新的β-内酰胺酶抑制剂已被批准或正在进行临床试验，但它们的活性谱并不能解决MDR病原体如鲍曼不动杆菌。本报告描述了广谱丝氨酸β-内酰胺酶抑制剂的合理设计和表征，该抑制剂有效抑制临床相关的A、C和D类β-内酰胺酶和青霉素结合蛋白，从而对肠杆菌科具有内在抗菌活性，并在广泛的MDR革兰氏阴性病原体中恢复β-内酰胺酶活性。最有前景的组合之一是舒巴坦-ETX 2514，其具有强效抗菌活性，体内抗MDR A的疗效。鲍曼不动杆菌感染和有前景的临床前安全性证明了其解决这一重大未满足的医疗需求的潜力。
Multidrug-resistant (MDR) bacterial infections are a serious threat to public health. Among the most alarming resistance trends is the rapid rise in the number and diversity of beta-lactamases, enzymes that inactivate beta-lactams, a class of antibiotics that has been a therapeutic mainstay for decades. Although several new beta-lactamase inhibitors have been approved or are in clinical trials, their spectra of activity do not address MDR pathogens such as Acinetobacter baumannii. This report describes the rational design and characterization of expanded-spectrum serine beta-lactamase inhibitors that potently inhibit clinically relevant class A, C and D beta-lactamases and penicillin-binding proteins, resulting in intrinsic antibacterial activity against Enterobacteriaceae and restoration of beta-lactam activity in a broad range of MDR Gramnegative pathogens. One of the most promising combinations is sulbactam-ETX2514, whose potent antibacterial activity, in vivo efficacy against MDR A. baumannii infections and promising preclinical safety demonstrate its potential to address this significant unmet medical need.