Aspergillomarasmine A overcomes metallo-b-lactamaseantibiotic resistance
Aspergillomarasmine A overcomes metallo-b-lactamaseantibiotic resistance
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发表时间：
2014
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通讯作者：
Andrew M. Q. King;Sarah A. Reid-Yu;Wenliang Wang;D. King;G. D. Pascale;N. Strynadka;T. Walsh;
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作者：
Andrew M. Q. King;Sarah A. Reid-Yu;Wenliang Wang;D. King;G. D. Pascale;N. Strynadka;T. Walsh;
耐碳青霉烯类革兰阴性菌的出现和传播是一个全球性的公共卫生问题。金属-b-内酰胺酶（MBL）如NDM-1的获得是碳青霉烯类耐药革兰氏阴性病原体出现的主要原因，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使用。迄今为止，尚未发现能够逆转耐药性并使耐药革兰氏阴性病原体对碳青霉烯类重新敏感的MBL的临床抑制剂，在此，我们鉴定了真菌天然产物曲霉毒胺A（AMA），其是NDM-1酶和另一种临床相关MBL，Vim-2的快速且有效的抑制剂。AMA也完全恢复了美罗培南对肠杆菌科、不动杆菌属的活性。和假单胞菌属（Pseudomonas spp.）具有Vim或NDM型等位基因。在感染了表达NDM-1的肺炎克雷伯菌的小鼠中，AMA有效地恢复了美罗培南的活性，表明AMA和碳青霉烯类抗生素的组合具有治疗潜力，可以解决MBL阳性碳青霉烯类耐药革兰氏阴性病原体的临床挑战。
The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. The acquisition of metallo-b-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenemresistant 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.