This product is used as an intermediate for the sythesis of novel β-lactam enhancers such as Zidebactamand WCK 5153.
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 Pseudomonas aeruginosa, 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 (mexR), porin-deficient (oprD), and AmpC-hyperproducing (dacB) derivatives of PAO1, and MBL-expressing clinical strains ST175 (blaVIM-2) and ST111 (blaVIM-1). 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 Ki [Kiapp] > 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 P. aeruginosa 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 P. aeruginosa infections, bypassing the need for MBL inhibition.
關(guān)鍵字： 1174020-25-7;阿維巴坦中間體6 ;
河北唯特醫(yī)藥科技有限公司專注于苯并雜環(huán)Block，抗生素增強(qiáng)劑（Antibiotic enhancer）的研發(fā)和生產(chǎn)，尤其以β內(nèi)酰胺酶抑制劑類管線的藥物為業(yè)務(wù)主線，提供阿維巴坦（Avibactam），瑞萊巴坦（Relebactam），齊德巴坦（Zidebactam），WCK-5153，等一系列β內(nèi)酰胺酶抑制劑的中間體，API的研發(fā)生產(chǎn)，技術(shù)服務(wù)和技術(shù)轉(zhuǎn)讓等一系列服務(wù)。