文献类型：期刊文献

英文题名：A dual-targeting antifungal is effective against multidrug-resistant human fungal pathogens

作者：Zhou, Min[1,2];Liu, Longqiang[2];Cong, Zihao[2];Jiang, Weinan[2];Xiao, Ximian[2];Xie, Jiayang[2];Luo, Zhengjie[2];Chen, Sheng[2];Wu, Yueming[2];Xue, Xinying[3,4];Shao, Ning[2];Liu, Runhui[1,2]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[2]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Frontiers Sci Ctr Materiobiol & Dynam Chem, Res Ctr Biomed Mat Minist Educ,Sch Mat Sci & Engn,, Shanghai, Peoples R China;[3]Capital Med Univ, Beijing Shijitan Hosp, Dept Resp & Crit Care, Beijing, Peoples R China;[4]Shandong Second Med Univ, Sch Clin Med, Weifang, Peoples R China

年份：2024

卷号：9

期号：5

外文期刊名：NATURE MICROBIOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001198537400002)】；

基金：This study was supported by the National Natural Science Foundation of China (number T2325010 (R.L.)), National Key Research and Development Program of China (2022YFC2303100 (R.L.)), National Natural Science Foundation of China (22075078 (R.L.), 22305082 (M.Z.), 52203162 (Y.W.), 82370005 (X.X.)), Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (Shanghai Municipal Education Commission) (R.L.), Open Research Fund of State Key Laboratory of Polymer Physics and Chemistry (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences) (R.L.) and the Open Project of Engineering Research Center of Dairy Quality and Safety Control Technology (Ministry of Education, R202201) (R.L.). We thank the Analysis and Testing Center of the East China University of Science and Technology for their help in the characterization. We also thank the Analysis and Testing Center of the School of Chemical Engineering, East China University of Science and Technology for the support. We thank the staff members of the Integrated Laser Microscopy System at the National Facility for Protein Science in Shanghai (NFPS), Zhangjiang Lab, China, for providing technical support and assistance in data collection and analysis.

语种：英文

摘要：Drug-resistant fungal infections pose a significant threat to human health. Dual-targeting compounds, which have multiple targets on a single pathogen, offer an effective approach to combat drug-resistant pathogens, although ensuring potent activity and high selectivity remains a challenge. Here we propose a dual-targeting strategy for designing antifungal compounds. We incorporate DNA-binding naphthalene groups as the hydrophobic moieties into the host defence peptide-mimicking poly(2-oxazoline)s. This resulted in a compound, (Gly0.8Nap0.2)20, which targets both the fungal membrane and DNA. This compound kills clinical strains of multidrug-resistant fungi including Candida spp., Cryptococcus neoformans, Cryptococcus gattii and Aspergillus fumigatus. (Gly0.8Nap0.2)20 shows superior performance compared with amphotericin B by showing not only potent antifungal activities but also high antifungal selectivity. The compound also does not induce antimicrobial resistance. Moreover, (Gly0.8Nap0.2)20 exhibits promising in vivo therapeutic activities against drug-resistant Candidaalbicans in mouse models of skin abrasion, corneal infection and systemic infection. This study shows that dual-targeting antifungal compounds may be effective in combating drug-resistant fungal pathogens and mitigating fungal resistance. A membrane- and DNA-targeting approach is used to design a compound that displays potent activity against multidrug-resistant fungal pathogens without inducing antifungal resistance.