Multivalent Display of Lipophilic DNA Binders for Dual-Selective Anti-Mycobacterium Peptidomimetics with Binary Mechanism of Action  

作　　者：Jianxue Wang Junfeng Song Xianhui Chen Rey-Ting Guo Yingjie Wang Guopu Huang Nan Zheng Peilei Hu Xinxin Feng Yugang Bai 

机构地区：[1]State Key Laboratory of Chem-/Bio-Sensing and Chemometrics,Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology,School of Chemistry and Chemical Engineering,Hunan University,Changsha,Hunan 410082 [2]State Key Laboratory of Biocatalysis and Enzyme Engineering,School of Life Sciences,Hubei University,Wuhan,Hubei 430062 [3]Institute of Systems and Physical Biology,Shenzhen Bay Laboratory,Shenzhen,Guangdong 518055 [4]Department of Polymer Science and Engineering,School of Chemical Engineering,Dalian University of Technology,Dalian,Liaoning 116024 [5]Hunan Institute for Tuberculosis Control,Hunan Chest Hospital,Changsha,Hunan 410013

出　　处：《CCS Chemistry》2022年第11期3573-3586,共14页中国化学会会刊（英文）

基　　金：This research was made possible as a result of the start-up funding from Hunan University,as a part of China’s Fundamental Research Funds for the Central Universities,the funding from the National Natural Science Foundation of China(grant nos.21877033,92163127,Y.B.,21807031,22177031,X.F.);the funding from the Natural Science Foundation of Hunan Province(grant no.2021JJ30088,Y.B.,2020JJ4177,X.F.);the Open Funding Project of the State Key Laboratory of Biocatalysis and Enzyme Engineering(Hubei University,SKLBEE2019003,X.F.).

摘　　要：We made oligoamidine-based peptidomimetics highly specific for mycobacteria eradication by introducing and arraying lipophilic DNA binding motifs on macromolecular backbones.The short poly(amidino-phenylindole)(PAPI)structures feature an alternating amphiphilic structure with cationic,lipophilic DNA-binding moieties,enabling fast and selective eradication of mycobacteria through binary,membrane-and DNA-selective mechanisms of action.More importantly,PAPIs address the primary treatment challenge by combating mycobacteria in eukaryotic cells and working as a sensitizer for conventional antibiotics,in bothways promoting more thorough removal of pathogens and reducing the mycobacteria’s resistance generation rate during treatment.Structural optimizationwas achieved to counter specific pathogens,including Mycobacterium tuberculosis,in the Mycobacterium genus.One of the hit peptidomimetics was evaluated in a zebrafish-based aquatic infection model using Mycobacterium fortuitum and a mice tail infection model using Mycobacterium marinum,both revealing excellent in vivo performance.

关 键 词：PEPTIDOMIMETIC MYCOBACTERIA antimicrobial membrane disruption DNA binding 

分 类 号：O62[理学—有机化学]