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Small Molecule Carboxylates Inhibit Metallo-β-lactamases and Resensitize Carbapenem-Resistant Bacteria to Meropenem.
ACS Infectious Diseases ( IF 5.3 ) Pub Date : 2020-03-31 , DOI: 10.1021/acsinfecdis.9b00459
Kamaleddin H M E Tehrani 1 , Nora C Brüchle 1 , Nicola Wade 1 , Vida Mashayekhi 2 , Diego Pesce 3, 4 , Matthijs J van Haren 1 , Nathaniel I Martin 1
Affiliation  

In the search for new inhibitors of bacterial metallo-β-lactamases (MBLs), a series of commonly used small molecule carboxylic acid derivatives were evaluated for their ability to inhibit New Delhi metallo-β-lactamase (NDM)-, Verona integron-encoded metallo-β-lactamase (VIM)-, and imipenemase (IMP)-type enzymes. Nitrilotriacetic acid (3) and N-(phosphonomethyl)iminodiacetic acid (5) showed promising activity especially against NDM-1 and VIM-2 with IC50 values in the low-to-sub μM range. Binding assays using isothermal titration calorimetry reveal that 3 and 5 bind zinc with high affinity with dissociation constant (Kd) values of 121 and 56 nM, respectively. The in vitro biological activity of 3 and 5 against E. coli expressing NDM-1 was evaluated in checkerboard format, demonstrating a strong synergistic relationship for both compounds when combined with Meropenem. Compounds 3 and 5 were then tested against 35 pathogenic strains expressing MBLs of the NDM, VIM, or IMP classes. Notably, when combined with Meropenem, compounds 3 and 5 were found to lower the minimum inhibitory concentration (MIC) of Meropenem up to 128-fold against strains producing NDM- and VIM-type enzymes.

中文翻译:

小分子羧酸盐抑制金属β-内酰胺酶并使耐碳青霉烯的细菌对美洛培南敏感。

在寻找细菌金属β-内酰胺酶(MBLs)的新抑制剂时,评估了一系列常用的小分子羧酸衍生物抑制维罗纳整合子编码的新德里金属β-内酰胺酶(NDM)的能力。金属β-内酰胺酶(VIM)和亚胺培南酶(IMP)型酶。亚硝基三乙酸(3)和N-(膦酰基甲基)亚氨基二乙酸(5)表现出良好的活性,尤其是对NDM-1和VIM-2的活性,其IC 50值在低至亚μM范围内。用等温滴定量热法进行的结合测定显示,35以高亲和力结合锌,且离解常数(K d)值分别为121和56 nM。在体外的生物活性35大肠杆菌表达NDM-1在棋盘格式进行了评价,这表明两种化合物强烈协同关系当与美罗培南组合。然后针对35种表达NDM,VIM或IMP类MBL的致病菌株测试化合物35。值得注意的是,当与美洛培南合用时,发现化合物35可以将美洛培南的最低抑菌浓度(MIC)降低至产生NDM和VIM型酶的菌株的128倍。
更新日期:2020-03-31
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