Infections caused by metallo-β-lactamase (MBL)-producing bacteria are emerging and carry a significant impact on patients' outcome. MBL producers are spread worldwide, both in community and hospital setting, with increasingly reported epidemic clusters and the search for MBL inhibitors is an important topic for public health. MBLs are zinc-dependent enzymes whose functioning can be hampered by zinc chelators. We evaluated the potential of six zinc chelators (disulfiram, nitroxoline, 5-amino-8-hydroxyquinoline, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA], cyclam, and N,N,N′,N′-tetrakis (2-pyridymethyl) ethylenediamine [TPEN]) in restoring carbapenem activity against MBL producers. Zinc chelators alone or in combination with meropenem against MBL-producing Klebsiella pneumoniae, Chryseobacterium indologenes, Elizabethkingia meningoseptica, and Stenotrophomonas maltophilia isolates were tested in vitro and in vivo (Galleria mellonella). In vitro experiments showed a synergistic activity between TPEN and meropenem toward all the strains. Nitroxoline alone retained activity against S. maltophilia, C. indologenes, and E. meningoseptica. In vivo experiments showed that TPEN or nitroxoline in combination with meropenem increased survival in larvae infected with E. meningoseptica, S. maltophilia, and K. pneumoniae. Based on our data, zinc chelators are potential carbapenem adjuvants molecules (restoring carbapenem activity) against MBL-sustained infections and could represent an interesting option for infections induced by these microorganisms.

中文翻译：

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锌螯合剂作为生产金属β-内酰胺酶的细菌的碳青霉烯佐剂：体外和体内评估。

由产生金属β-内酰胺酶（MBL）的细菌引起的感染正在出现，并对患者的预后产生重大影响。MBL生产者遍及社区和医院，遍布世界各地，流行病的报道越来越多，寻找MBL抑制剂是公共卫生的重要课题。MBL是锌依赖性酶，其功能可能会受到锌螯合剂的阻碍。我们评估了六种锌螯合剂的潜力（双硫仑，硝唑啉，5-氨基-8-羟基喹啉，1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸[DOTA]，cyclam和N， N，N'，N'-四（2-吡啶甲基）乙二胺[TPEN]）恢复碳青霉烯对MBL生产者的活性。锌螯合剂单独使用或与美罗培南联合使用以对抗MBL产生肺炎克雷伯氏菌，金黄indologenes，Elizabethkingia meningoseptica，和嗜麦芽的分离物测试在体外和体内（大蜡螟）。体外实验显示，TPEN和美罗培南对所有菌株均具有协同活性。单独使用甲氧沙林可保持抵抗嗜麦芽糖链球菌，产臭梭菌和脑膜炎大肠杆菌的活性。体内实验表明，TPEN或硝氧环与美罗培南合用可增加感染脑膜炎败血性大肠杆菌，嗜麦芽孢杆菌和肺炎克雷伯菌的幼虫的存活率。。根据我们的数据，锌螯合剂是潜在的碳青霉烯类佐剂分子（恢复碳青霉烯类活性），可抵抗MBL持续感染，并且可能代表这些微生物诱导的感染的有趣选择。