한빛사논문
Yoon Jee Lee 1, Jin Kyung Kim 2 3 4, Chan Hoon Jung 1, Young Jae Kim 2 3 4, Eui Jung Jung 1, Su Hyun Lee 1, Ha Rim Choi 1, Yeon Sung Son 5, Sang Mi Shim 1, Sang Min Jeon 2 3 4, Jin Ho Choe 2 3 4, Sang-Hee Lee 6, Jake Whang 7, Kyung-Cheol Sohn 3 8, Gang Min Hur 3 8, Hyun Tae Kim 9, Jinki Yeom 1 10, Eun-Kyeong Jo 2 3 4*, Yong Tae Kwon 1 9 11 12*
1Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.
2Department of Microbiology, Chungnam National University School of Medicine, Daejeon, Korea.
3Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea.
4Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, Korea.
5Neuroscience Research Institute, Medical Research Center, College of Medicine, Seoul National University, Seoul, Republic of Korea.
6Center for Research Equipment, Korea Basic Science Institute, Cheongju, Korea.
7Korea Mycobacterium Resource Center (KMRC) & Basic Research Section, The Korean Institute of Tuberculosis (KIT), Cheongju, Korea.
8Department of Pharmacology, Chungnam National University School of Medicine, Daejeon, Korea.
9Chemistry R&D Center, AUTOTAC Bio Inc, Seoul, Republic of Korea.
10Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, Republic of Korea.
11SNU Dementia Research Center, College of Medicine, Seoul National University, Seoul, Republic of Korea.
12Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea.
*Corresponding author.
Abstract
The N-degron pathway is a proteolytic system in which the N-terminal degrons (N-degrons) of proteins, such as arginine (Nt-Arg), induce the degradation of proteins and subcellular organelles via the ubiquitin-proteasome system (UPS) or macroautophagy/autophagy-lysosome system (hereafter autophagy). Here, we developed the chemical mimics of the N-degron Nt-Arg as a pharmaceutical means to induce targeted degradation of intracellular bacteria via autophagy, such as Salmonella enterica serovar Typhimurium (S. Typhimurium), Escherichia coli, and Streptococcus pyogenes as well as Mycobacterium tuberculosis (Mtb). Upon binding the ZZ domain of the autophagic cargo receptor SQSTM1/p62 (sequestosome 1), these chemicals induced the biogenesis and recruitment of autophagic membranes to intracellular bacteria via SQSTM1, leading to lysosomal degradation. The antimicrobial efficacy was independent of rapamycin-modulated core autophagic pathways and synergistic with the reduced production of inflammatory cytokines. In mice, these drugs exhibited antimicrobial efficacy for S. Typhimurium, Bacillus Calmette–Guérin (BCG), and Mtb as well as multidrug-resistant Mtb and inhibited the production of inflammatory cytokines. This dual mode of action in xenophagy and inflammation significantly protected mice from inflammatory lesions in the lungs and other tissues caused by all the tested bacterial strains. Our results suggest that the N-degron pathway provides a therapeutic target in host-directed therapeutics for a broad range of drug-resistant intracellular pathogens.
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