Abstract

Background

Carbapenemase-producing Enterobacterales represent a major therapeutic challenge. MBLs, requiring zinc at their catalytic site, could be inhibited by meso-dimercaptosuccinic acid (DMSA), a heavy metal chelator already widely used for treating lead intoxication.

Objectives

To evaluate the activity of carbapenems alone or combined with DMSA against MBL-producing Escherichia coli in a severe murine peritonitis model.

Methods

Isogenic strains of wild-type E. coli CFT073 producing the MBLs NDM-1, VIM-2 and IMP-1, and the control serine carbapenemases OXA-48 and KPC-3 were constructed. MIC determinations and time–kill assays were performed for imipenem, meropenem and ertapenem alone or in combination with DMSA. Infected mice were treated intraperitoneally for 24 h with imipenem, DMSA or their combination. Bacterial counts in peritoneal fluid and spleen were assessed at 24 h.

Results

DMSA in combination with each carbapenem caused a significant decrease in the MICs for all MBL-producing strains, in a concentration-dependent manner, but did not provide benefit against non-MBL strains. In mice infected with the NDM-1-producing strain, the combination of imipenem and DMSA significantly reduced bacterial counts in peritoneal fluid (P = 0.0006) and spleen (P < 0.0001), as compared with imipenem alone, with no benefit against the KPC-3-producing and CFT073 strains. DMSA concentrations in plasma of mice were comparable to those obtained in humans with a standard oral dose.

Conclusions

DMSA restores the activity of carbapenems against MBL-producing strains, and its combination with carbapenems appears to be a promising strategy for the treatment of NDM-producing E. coli infections.

中文翻译：

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二巯基琥珀酸与碳青霉烯类药物联合使用可在体外和鼠类腹膜炎中产生或不产生金属β-内酰胺酶的大肠杆菌同基因菌株。

摘要

背景

产生碳青霉烯酶的肠杆菌代表了主要的治疗挑战。甲基二巯基琥珀酸（DMSA）可以抑制在催化位点需要锌的MBL，DMSA是一种已经广泛用于治疗铅中毒的重金属螯合剂。

目标

在严重的鼠腹膜炎模型中评估碳青霉烯类单独或与DMSA联合使用对产生MBL的大肠杆菌的活性。

方法

构建了产生MBL NDM-1，VIM-2和IMP-1的野生型大肠杆菌CFT073的同基因菌株，以及对照丝氨酸碳青霉烯酶OXA-48和KPC-3。单独或与DMSA联合使用亚胺培南，美罗培南和厄他培南的MIC测定和杀灭时间的测定法。用亚胺培南，DMSA或其组合对感染的小鼠进行腹膜内治疗24小时。在24小时评估腹膜液和脾脏中的细菌计数。

结果

DMSA与每种碳青霉烯类药物的结合导致所有MBL产生菌株的MIC均以浓度依赖的方式显着降低，但未对非MBL菌株产生益处。与单独使用亚胺培南相比，在感染产生NDM-1菌株的小鼠中，亚胺培南和DMSA的组合显着降低了腹膜液（P =  0.0006）和脾脏中细菌计数（P <  0.0001），对KPC无益处产生-3-和CFT073菌株。小鼠血浆中的DMSA浓度与标准口服剂量的人血浆中的DMSA浓度相当。

结论

DMSA恢复了碳青霉烯类抗产生MBL的菌株的活性，它与碳青霉烯类的组合似乎是治疗产生NDM的大肠杆菌感染的有前途的策略。