The autophagy-targeting compound V46 enhances antimicrobial responses to Mycobacteroides abscessus by activating transcription factor EB

Asmita Sapkota; Eun-Jin Park; Young Jae Kim; Jong Beom Heo; Thanh Quang Nguyen; Bo Eun Heo; Jin Kyung Kim; Sang-Hee Lee; Soo In Kim; Yoon-Jung Choi; Taylor Roh; Sang Min Jeon; Marnpyung Jang; Hae Joon Heo; Jake Whang; Seungwha Paik; Jae-Min Yuk; Jin-Man Kim; Gyu Yong Song; Jichan Jang; Eun-Kyeong Jo

Biomedicine & Pharmacotherapy (Oct 2024)

The autophagy-targeting compound V46 enhances antimicrobial responses to Mycobacteroides abscessus by activating transcription factor EB

Asmita Sapkota,
Eun-Jin Park,
Young Jae Kim,
Jong Beom Heo,
Thanh Quang Nguyen,
Bo Eun Heo,
Jin Kyung Kim,
Sang-Hee Lee,
Soo In Kim,
Yoon-Jung Choi,
Taylor Roh,
Sang Min Jeon,
Marnpyung Jang,
Hae Joon Heo,
Jake Whang,
Seungwha Paik,
Jae-Min Yuk,
Jin-Man Kim,
Gyu Yong Song,
Jichan Jang,
Eun-Kyeong Jo

Affiliations

Asmita Sapkota: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea
Eun-Jin Park: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea; Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea
Young Jae Kim: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea; Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea
Jong Beom Heo: Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; College of Pharmacy, Chungnam National University, Daejeon, South Korea
Thanh Quang Nguyen: Division of Life Science, Department of Bio & Medical Big Data (BK21 Four Program), Research Institute of Life Science, Gyeongsang National University, Jinju, South Korea
Bo Eun Heo: Division of Life Science, Department of Bio & Medical Big Data (BK21 Four Program), Research Institute of Life Science, Gyeongsang National University, Jinju, South Korea
Jin Kyung Kim: Department of Microbiology, Keimyung University, School of Medicine, Daegu, South Korea
Sang-Hee Lee: Center for Research Equipment, Korea Basic Science Institute, Cheongju, Chungbuk, South Korea
Soo In Kim: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea; Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea
Yoon-Jung Choi: Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; College of Pharmacy, Chungnam National University, Daejeon, South Korea
Taylor Roh: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea; Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea
Sang Min Jeon: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea; Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea
Marnpyung Jang: College of Medicine, Chungnam National University, Daejeon, South Korea
Hae Joon Heo: Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; College of Pharmacy, Chungnam National University, Daejeon, South Korea
Jake Whang: Korea Mycobacterium Resource Center & Basic Research Section, The Korean Institute of Tuberculosis, Cheongju, South Korea
Seungwha Paik: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea
Jae-Min Yuk: Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea; Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea
Jin-Man Kim: Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea; Department of Pathology, College of Medicine, Chungnam National University, Daejeon, South Korea
Gyu Yong Song: Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; College of Pharmacy, Chungnam National University, Daejeon, South Korea; Corresponding author at: College of Pharmacy, Chungnam National University, Daejeon, South Korea.
Jichan Jang: Division of Life Science, Department of Bio & Medical Big Data (BK21 Four Program), Research Institute of Life Science, Gyeongsang National University, Jinju, South Korea; Corresponding author at: Division of Life Science, Department of Bio & Medical Big Data (BK21 Four Program), Research Institute of Life Science, Gyeongsang National University, Jinju, South Korea.
Eun-Kyeong Jo: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea; Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea; Corresponding author at: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea.

Journal volume & issue: Vol. 179
p. 117313

Abstract

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Mycobacteroides abscessus (Mabc) is a rapidly growing nontuberculous mycobacterium that poses a considerable challenge as a multidrug-resistant pathogen causing chronic human infection. Effective therapeutics that enhance protective immune responses to Mabc are urgently needed. This study introduces trans-3,5,4′-trimethoxystilbene (V46), a novel resveratrol analogue with autophagy-activating properties and antimicrobial activity against Mabc infection, including multidrug-resistant strains. Among the resveratrol analogues tested, V46 significantly inhibited the growth of both rough and smooth Mabc strains, including multidrug-resistant strains, in macrophages and in the lungs of mice infected with Mabc. Additionally, V46 substantially reduced Mabc-induced levels of pro-inflammatory cytokines and chemokines in both macrophages and during in vivo infection. Mechanistic analysis showed that V46 suppressed the activation of the protein kinase B/Akt-mammalian target of rapamycin signaling pathway and enhanced adenosine monophosphate-activated protein kinase signaling in Mabc-infected cells. Notably, V46 activated autophagy and the nuclear translocation of transcription factor EB, which is crucial for antimicrobial host defenses against Mabc. Furthermore, V46 upregulated genes associated with autophagy and lysosomal biogenesis in Mabc-infected bone marrow-derived macrophages. The combination of V46 and rifabutin exerted a synergistic antimicrobial effect. These findings identify V46 as a candidate host-directed therapeutic for Mabc infection that activates autophagy and lysosomal function via transcription factor EB.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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