Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance

摘要

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.%本期封面所示为海洋真菌Aspergillus versicolor 的分生孢子梗和孢子（用乳酸酚棉蓝染色）。被携带metallo- β -lactamases (如NDM-1和VIM)的革兰氏阴性病原体感染，是一个不断发展的公共卫生问题，使得用青霉素、头孢菌素和carbapenem类抗生素来治疗感染受到威胁。在这篇论文中，Gerard Wright及同事报告了在从环境微生物获得的溶于DMSO的大量天然产物提取物中对NDM-1的天然抑制剂所做的一个筛选。其中的一种提取物（来自A. versicolor)表现出特别强的抗NDM-1活性，被识别出是aspergillomarasmine A(AMA),后者是大约50年前首次被报告的一种与叶子枯萎相关的天然产物。AMA对NDM-1和VIM-2来说都是一种迅速的、强效的抑制剂，本文作者发现AMA在体外和体内都能完全恢复针对拥有VIM-型或NDM-型抗性基因的细菌病原体的抗菌功效。