Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin
Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin
复制标题
DOI：
10.1093/cid/ciz826
复制
发表时间：
2019-12-01
影响因子：
11.8
通讯作者：
Yamawaki, Kenji
中科院分区：
文献类型：
--
作者：
Sato, Takafumi;Yamawaki, Kenji
抗生素耐药性的出现是全球范围内的一个重大公共卫生问题，特别是对于由碳青霉烯类耐药革兰氏阴性病原体引起的医疗保健相关感染。头孢地罗可是一种新型的铁载体头孢菌素，靶向革兰氏阴性菌，包括碳青霉烯耐药菌株。头孢德罗可的结构特征与头孢他啶和头孢吡肟相似，这使得头孢德罗可耐受β-内酰胺酶的水解。独特的化学成分是在C-3侧链上添加了儿茶酚部分，其螯合铁并模拟天然存在的铁载体分子。铁螯合后，头孢地罗可通过专门的铁转运蛋白通道主动转运穿过细菌细胞的外膜至周质空间。此外，已证明头孢地罗可对丝氨酸和金属β-内酰胺酶水解具有结构稳定性，包括临床相关的碳青霉烯酶，如肺炎克雷伯菌碳青霉烯酶、苯唑西林碳青霉烯酶-48和新德里金属β-内酰胺酶。Cefiderocol已证明具有良好的体外抗菌和杀菌活性，这与其在几种动物模型中的体内功效相关。本文综述了头孢地罗可的发现和化学，以及最近进行的研究中头孢地罗可的一些关键微生物和体内研究结果。
The emergence of antimicrobial resistance is a significant public health issue worldwide, particularly for healthcare-associated infections caused by carbapenem-resistant gram-negative pathogens. Cefiderocol is a novel siderophore cephalosporin targeting gram-negative bacteria, including strains with carbapenem resistance. The structural characteristics of cefiderocol show similarity to both ceftazidime and cefepime, which enable cefiderocol to withstand hydrolysis by beta-lactamases. The unique chemical component is the addition of a catechol moiety on the C-3 side chain, which chelates iron and mimics naturally occurring siderophore molecules. Following the chelation of iron, cefiderocol is actively transported across the outer membrane of the bacterial cell to the periplasmic space via specialized iron transporter channels. Furthermore, cefiderocol has demonstrated structural stability against hydrolysis by both serine- and metallo-beta-lactamases, including clinically relevant carbapenemases such as Klebsiella pneumoniae carbapenemase, oxacillin carbapenemase-48, and New Delhi metallo-beta-lactamase. Cefiderocol has demonstrated promising in vitro antibacterial and bactericidal activity, which correlates with its in vivo efficacy in several animal models. This article reviews the discovery and chemistry of cefiderocol, as well as some of the key microbiological and in vivo findings on cefiderocol from recently conducted investigations.