Discovery of a Novel Metallo-β-Lactamase Inhibitor That Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae
Discovery of a Novel Metallo-β-Lactamase Inhibitor That Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae
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DOI：
10.1128/aac.00074-18
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发表时间：
2018-05-01
影响因子：
4.9
通讯作者：
Lemonnier, Marc
中科院分区：
文献类型：
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作者：
Everett, Martin;Sprynski, Nicolas;Lemonnier, Marc
由碳青霉烯类耐药肠杆菌科（CRE）引起的感染日益普遍，并且已成为全球范围内对人类健康的主要威胁。碳青霉烯类耐药性主要由β-内酰胺酶的获得驱动，β-内酰胺酶能够降解碳青霉烯类抗生素（因此称为碳青霉烯酶）并导致高水平的耐药性和治疗失败。临床相关的碳青霉烯酶包括丝氨酸β-内酰胺酶（SBL;例如，KPC-2和OXA-48）和金属-β-内酰胺酶（MBL），如NDM-1。产MBL菌株在许多亚洲国家的社区内流行，已成功传播到世界各地，并导致许多重大的CRE爆发。最近批准的β-内酰胺抗生素与β-内酰胺酶抑制剂的组合仅对产生SBL的病原体有效。因此，迫切需要特异性靶向MBL并恢复碳青霉烯类对产MBL的CRE病原体的功效的新药。在这里，我们报告了一种新的MBL抑制剂，ANT 431，可以增强美罗培南（MEM）对广泛的MBL生产CRE的活性，并恢复其对大肠杆菌NDM-1生产菌株在小鼠大腿感染模型的疗效的发现。这是一个强有力的起点，为化学铅优化计划，可以提供一流的MBL抗生素-碳青霉烯组合。这将补充现有的打击CRE的武器，并解决一个重要的和日益增长的未满足的医疗需求。
Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent and have become a major worldwide threat to human health. Carbapenem resistance is driven primarily by the acquisition of beta-lactamase enzymes, which are able to degrade carbapenem antibiotics (hence termed carbapen-emases) and result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine beta-lactamases (SBLs; e.g., KPC-2 and OXA-48) and metallo-beta-lactamases (MBLs), such as NDM-1. MBL-producing strains are endemic within the community in many Asian countries, have successfully spread worldwide, and account for many significant CRE outbreaks. Recently approved combinations of beta-lactam antibiotics with beta-lactamase inhibitors are active only against SBL-producing pathogens. Therefore, new drugs that specifically target MBLs and which restore carbapenem efficacy against MBL-producing CRE pathogens are urgently needed. Here we report the discovery of a novel MBL inhibitor, ANT431, that can potentiate the activity of meropenem (MEM) against a broad range of MBL-producing CRE and restore its efficacy against an Escherichia coli NDM-1-producing strain in a murine thigh infection model. This is a strong starting point for a chemistry lead optimization program that could deliver a first-in-class MBL inhibitor-carbapenem combination. This would complement the existing weaponry against CRE and address an important and growing unmet medical need.