He Yan, Zhou Shupeng, Sun Weiguang, Li Qin, Wang Jianping, Zhang Jinwen
Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
J Glob Antimicrob Resist. 2022 Mar;28:216-222. doi: 10.1016/j.jgar.2021.12.019. Epub 2022 Jan 10.
Bacterial strains that produce New Delhi metal-β-lactamase 1 (NDM-1) are a worldwide health threat. It remains a challenging task to find a potent NDM-1 inhibitor for clinical practice.
Molecular docking and virtual screening of an in-house fungal natural product database for NDM-1 inhibitors were performed. Based on the screening results, the affinity and inhibition ability of potential NDM-1 inhibitors were determined using purified NDM-1. The efficacy of compounds in combination with four β-lactam antibiotics (meropenem, imipenem, ceftriaxone and ampicillin) was evaluated. Morphological changes in Klebsiella pneumoniae ATCC BAA-2146 after treatment with the compounds were visualised by transmission electron microscopy.
In silico screening led to the identification of four fungal products as potential NDM-1 inhibitors. Emerione A (1), a methylated polyketide with bicyclo[4.2.0]octene and 3,6-dioxabicyclo[3.1.0]hexane functionalities, has significant activity in cells (K = 11.8 ± 0.6 μM; IC = 12.1 ± 0.9 μM) and potentiates the activity of meropenem against two kinds of NDM-1-producing Enterobacteriaceae. To the best of our knowledge, emerione A (1) is the second fungal metabolite reported to exhibit NMD-1 inhibitory activity. According to the structural novelty of our database, we also found a new structural compound, asperfunolone A (2), with potential NMD-1 inhibitory activity.
Considering the low toxicity of emerione A (1), it may represent a potential lead compound for anti-NDM-1 drug development.
产新德里金属β-内酰胺酶1（NDM-1）的细菌菌株对全球健康构成威胁。寻找一种有效的NDM-1抑制剂用于临床实践仍然是一项具有挑战性的任务。
对内部真菌天然产物数据库进行分子对接和虚拟筛选以寻找NDM-1抑制剂。基于筛选结果，使用纯化的NDM-1测定潜在NDM-1抑制剂的亲和力和抑制能力。评估化合物与四种β-内酰胺抗生素（美罗培南、亚胺培南、头孢曲松和氨苄西林）联合使用的效果。用透射电子显微镜观察化合物处理后肺炎克雷伯菌ATCC BAA-2146的形态变化。
计算机模拟筛选鉴定出四种真菌产物为潜在的NDM-1抑制剂。Emerione A（1）是一种具有双环[4.2.0]辛烯和3,6-二氧杂双环[3.1.0]己烷官能团的甲基化聚酮化合物，在细胞中具有显著活性（K = 11.8±0.6μM；IC = 12.1±0.9μM），并增强美罗培南对两种产NDM-1肠杆菌科细菌的活性。据我们所知，emerione A（1）是第二种被报道具有NMD-1抑制活性的真菌代谢产物。根据我们数据库的结构新颖性，我们还发现了一种具有潜在NMD-1抑制活性的新结构化合物，曲霉醇A（2）。
考虑到emerione A（1）的低毒性，它可能代表抗NDM-1药物开发的潜在先导化合物。
