WCK 5107（齐德巴坦）和WCK 5153是新型PBP2抑制剂，对铜绿假单胞菌表现出强大的“β-内酰胺增强剂”活性，包括产多重耐药金属β-内酰胺酶的高风险克隆株。
WCK 5107 (Zidebactam) and WCK 5153 Are Novel Inhibitors of PBP2 Showing Potent "β-Lactam Enhancer" Activity against Pseudomonas aeruginosa, Including Multidrug-Resistant Metallo-β-Lactamase-Producing High-Risk Clones.
作者信息
Moya Bartolome, Barcelo Isabel M, Bhagwat Sachin, Patel Mahesh, Bou German, Papp-Wallace Krisztina M, Bonomo Robert A, Oliver Antonio
机构信息
Servicio de Microbiología and Unidad de Investigación, Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca, Spain
Servicio de Microbiología and Unidad de Investigación, Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca, Spain.
出版信息
Antimicrob Agents Chemother. 2017 May 24;61(6). doi: 10.1128/AAC.02529-16. Print 2017 Jun.
Zidebactam and WCK 5153 are novel β-lactam enhancers that are bicyclo-acyl hydrazides (BCH), derivatives of the diazabicyclooctane (DBO) scaffold, targeted for the treatment of serious infections caused by highly drug-resistant Gram-negative pathogens. In this study, we determined the penicillin-binding protein (PBP) inhibition profiles and the antimicrobial activities of zidebactam and WCK 5153 against , including multidrug-resistant (MDR) metallo-β-lactamase (MBL)-producing high-risk clones. MIC determinations and time-kill assays were conducted for zidebactam, WCK 5153, and antipseudomonal β-lactams using wild-type PAO1, MexAB-OprM-hyperproducing (), porin-deficient (), and AmpC-hyperproducing () derivatives of PAO1, and MBL-expressing clinical strains ST175 () and ST111 (). Furthermore, steady-state kinetics was used to assess the inhibitory potential of these compounds against the purified VIM-2 MBL. Zidebactam and WCK 5153 showed specific PBP2 inhibition and did not inhibit VIM-2 (apparent [] > 100 μM). MICs for zidebactam and WCK 5153 ranged from 2 to 32 μg/ml (amdinocillin MICs > 32 μg/ml). Time-kill assays revealed bactericidal activity of zidebactam and WCK 5153. LIVE-DEAD staining further supported the bactericidal activity of both compounds, showing spheroplast formation. Fixed concentrations (4 or 8 μg/ml) of zidebactam and WCK 5153 restored susceptibility to all of the tested β-lactams for each of the mutant strains. Likewise, antipseudomonal β-lactams (CLSI breakpoints), in combination with 4 or 8 μg/ml of zidebactam or WCK 5153, resulted in enhanced killing. Certain combinations determined full bacterial eradication, even with MDR MBL-producing high-risk clones. β-Lactam-WCK enhancer combinations represent a promising β-lactam "enhancer-based" approach to treat MDR infections, bypassing the need for MBL inhibition.
齐德巴坦和WCK 5153是新型β-内酰胺增强剂，属于双环酰基肼（BCH），是二氮杂双环辛烷（DBO）支架的衍生物，旨在治疗由高度耐药革兰氏阴性病原体引起的严重感染。在本研究中，我们测定了齐德巴坦和WCK 5153对包括产多药耐药（MDR）金属β-内酰胺酶（MBL）的高风险克隆在内的多种菌株的青霉素结合蛋白（PBP）抑制谱和抗菌活性。使用野生型PAO1、MexAB-OprM高表达（）、孔蛋白缺陷（）和AmpC高表达（）的PAO1衍生物以及表达MBL的临床菌株ST175（）和ST111（），对齐德巴坦、WCK 5153和抗假单胞菌β-内酰胺进行了最低抑菌浓度（MIC）测定和时间杀菌试验。此外，采用稳态动力学评估了这些化合物对纯化的VIM-2 MBL的抑制潜力。齐德巴坦和WCK 5153表现出对PBP2的特异性抑制，且不抑制VIM-2（表观[]＞100μM）。齐德巴坦和WCK 5153的MIC范围为2至32μg/ml（氨曲南MIC＞32μg/ml）。时间杀菌试验显示齐德巴坦和WCK 5153具有杀菌活性。活死染色进一步支持了这两种化合物的杀菌活性，显示出原生质球形成。固定浓度（4或8μg/ml）的齐德巴坦和WCK 5153恢复了每种突变菌株对所有测试β-内酰胺的敏感性。同样，抗假单胞菌β-内酰胺（CLSI断点）与4或8μg/ml的齐德巴坦或WCK 5153联合使用，增强了杀菌效果。某些组合甚至能完全根除细菌，即使是对于产MDR MBL的高风险克隆。β-内酰胺-WCK增强剂组合代表了一种有前景的基于β-内酰胺“增强剂”的方法来治疗MDR感染，无需抑制MBL。
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