Indiana University Bloomington, Department of Biology, Indiana University, Bloomington, IN, USA.
Antimicrobial Development Specialists, LLC, Nyack, NY, USA.
Nat Rev Microbiol. 2019 May;17(5):295-306. doi: 10.1038/s41579-019-0159-8.
Resistance to β-lactam antibiotics in Gram-negative bacteria is commonly associated with production of β-lactamases, including extended-spectrum β-lactamases (ESBLs) and carbapenemases belonging to different molecular classes: those with a catalytically active serine and those with at least one active-site Zn to facilitate hydrolysis. To counteract the hydrolytic activity of these enzymes, combinations of a β-lactam with a β-lactamase inhibitor (BLI) have been clinically successful. However, some β-lactam-BLI combinations have lost their effectiveness against prevalent Gram-negative pathogens that produce ESBLs, carbapenemases or multiple β-lactamases in the same organism. In this Review, descriptions are provided for medically relevant β-lactamase families and various BLI combinations that have been developed or are under development. Recently approved inhibitor combinations include the inhibitors avibactam and vaborbactam of the diazabicyclooctanone and boronic acid inhibitor classes, respectively, as new scaffolds for future inhibitor design.
革兰氏阴性菌对β-内酰胺类抗生素的耐药性通常与β-内酰胺酶的产生有关，包括属于不同分子类别的扩展谱β-内酰胺酶（ESBLs）和碳青霉烯酶：那些具有催化活性丝氨酸的酶和那些至少具有一个活性位点 Zn 以促进水解的酶。为了抵消这些酶的水解活性，已经在临床上成功地将β-内酰胺与β-内酰胺酶抑制剂（BLI）联合使用。然而，一些β-内酰胺-BLI 联合用药对流行的革兰氏阴性病原体已经失去了效果，这些病原体在同一生物体中产生 ESBLs、碳青霉烯酶或多种β-内酰胺酶。在这篇综述中，提供了与医学相关的β-内酰胺酶家族的描述以及已经开发或正在开发的各种 BLI 联合用药。最近批准的抑制剂联合用药包括分别属于二氮杂双环辛酮和硼酸抑制剂类别的抑制剂阿维巴坦和沃巴坦，它们是未来抑制剂设计的新支架。
