An aryl isonitrile compound with an improved physicochemical profile that is effective in two mouse models of multidrug-resistant Staphylococcus aureus infection
An aryl isonitrile compound with an improved physicochemical profile that is effective in two mouse models of multidrug-resistant Staphylococcus aureus infection
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DOI：
10.1016/j.jgar.2019.04.016
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发表时间：
2019-12-01
影响因子：
4.6
通讯作者：
Seleem, Mohamed N.
中科院分区：
文献类型：
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作者：
Mohammad, Haroon;Kyei-Baffour, Kwaku;Seleem, Mohamed N.
目的：本研究的目的是研究合成芳基异腈化合物 (35) 的抗菌活性，该化合物是作为化合物库的一部分而开发的，旨在鉴定对耐甲氧西林金黄色葡萄球菌 (MRSA) 有效的新型抗菌剂。方法：通过肉汤微量稀释测定评估化合物 35 对 MRSA 分离株的抗菌活性，并使用 MTS 测定评估对哺乳动物角质形成细胞的毒性。进行多步耐药性选择测定来研究MRSA对35的耐药性发展。采用Caco-2双向渗透性测定来评估35渗透穿过胃肠道的能力，并将化合物35与人肝微粒体一起孵育以确定对肝脏代谢的敏感性。最后，在简单的MRSA皮肤感染小鼠模型和MRSA中性粒细胞减少性大腿感染小鼠模型中对化合物35进行了评估。结果：化合物35在2-4μM浓度下抑制MRSA临床分离株的生长，并且对人角质形成细胞无毒。在 10 次连续传代后，没有观察到 MRSA 针对化合物 35 的耐药性形成。在小鼠皮肤伤口模型中，化合物 35 显着降低了 MRSA 的负担，类似于抗生素夫西地酸。相对于第一代先导化合物，化合物 35 在渗透性和肝代谢稳定性（半衰期 >11 小时）方面均表现出显着改善。在中性粒细胞减少性大腿感染小鼠模型中，化合物 35 成功降低了免疫功能低下小鼠的 MRSA 负担。结论：综上所述，化合物 35 被鉴定为一种新的芳基异腈先导化合物，值得作为新型抗菌剂进行进一步研究。 (C) 2019 年国际抗菌化疗协会。由爱思唯尔有限公司出版。保留所有权利。
Objectives: The aim of this study was to investigate the antibacterial activity of a synthetic aryl isonitrile compound (35) that was developed as part of a compound library to identify new antibacterial agents effective against methicillin-resistant Staphylococcus aureus (MRSA).Methods: Compound 35 was evaluated against MRSA isolates by the broth microdilution assay and for toxicity to mammalian keratinocytes using the MTS assay. A multistep resistance selection assay was conducted to investigate MRSA resistance development to 35. A Caco-2 bidirectional permeability assay was employed to evaluate the ability of 35 to permeate across the gastrointestinal tract, and compound 35 was incubated with human liver microsomes to determine susceptibility to hepatic metabolism. Finally, compound 35 was evaluated in an uncomplicated MRSA skin infection mouse model and an MRSA neutropenic thigh infection mouse model.Results: Compound 35 inhibited the growth of MRSA clinical isolates at 2-4 mu M and was non-toxic to human keratinocytes. No resistance formation was observed with MRSA against compound 35 after 10 serial passages. In a murine skin wound model, compound 35 significantly reduced the burden of MRSA, similar to the antibiotic fusidic acid. Compound 35 exhibited a marked improvement both in permeability and stability to hepatic metabolism (half-life >11 h) relative to the first-generation lead compound. In a neutropenic thigh infection mouse model, compound 35 successfully reduced the burden of MRSA in immunocompromised mice.Conclusion: In summary, compound 35 was identified as a new lead aryl isonitrile compound that warrants further investigation as a novel antibacterial agent. (C) 2019 International Society for Antimicrobial Chemotherapy. Published by Elsevier Ltd. All rights reserved.