1] M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada [2] Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
Nature. 2014 Jun 26;510(7506):503-6. doi: 10.1038/nature13445.
The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. The acquisition of metallo-β-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenem-resistant Gram-negative pathogens that threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. To date, a clinical inhibitor of MBLs that could reverse resistance and re-sensitize resistant Gram-negative pathogens to carbapenems has not been found. Here we have identified a fungal natural product, aspergillomarasmine A (AMA), that is a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant MBL, VIM-2. AMA also fully restored the activity of meropenem against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp. possessing either VIM or NDM-type alleles. In mice infected with NDM-1-expressing Klebsiella pneumoniae, AMA efficiently restored meropenem activity, demonstrating that a combination of AMA and a carbapenem antibiotic has therapeutic potential to address the clinical challenge of MBL-positive carbapenem-resistant Gram-negative pathogens.
碳青霉烯类耐药革兰氏阴性病原体的出现和传播是一个全球性的公共卫生问题。金属β-内酰胺酶（MBLs）如 NDM-1 的获得是导致碳青霉烯类耐药革兰氏阴性病原体出现的主要原因之一，这些病原体威胁到青霉素、头孢菌素和碳青霉烯类抗生素治疗感染的效果。迄今为止，尚未发现能够逆转 MBL 耐药性并使耐药革兰氏阴性病原体重新对碳青霉烯类敏感的 MBL 临床抑制剂。在这里，我们发现了一种真菌天然产物，aspergillomarasmine A（AMA），它是 NDM-1 酶和另一种临床相关 MBL，VIM-2 的快速而有效的抑制剂。AMA 还完全恢复了美罗培南对携带 VIM 或 NDM 型等位基因的肠杆菌科、不动杆菌属和假单胞菌属的活性。在携带 NDM-1 表达的肺炎克雷伯菌感染的小鼠中，AMA 有效地恢复了美罗培南的活性，这表明 AMA 和碳青霉烯类抗生素的联合使用具有治疗 MBL 阳性碳青霉烯类耐药革兰氏阴性病原体的临床潜力。
