Jwa-Jin Kim^{1, 5, 10}, Hye-Mi Lee^{1, 5, 10}, Dong-Min Shin^{1, 5}, Wonho Kim⁶, Jae-Min Yuk^{1, 5}, Hyo Sun Jin^{1, 5}, Sang-Hee Lee^{2, 5, 11}, Guang-Ho Cha³, Jin-Man Kim^{2, 5}, Zee-Won Lee⁷, Sung Jae Shin^{1, 5, 12}, Heekyung Yoo⁸, Young Kil Park⁸, Jin Bong Park^{4, 5}, JongKyeong Chung⁶, Tamotsu Yoshimori⁹, Eun-Kyeong Jo^{1, 5, *}

¹ Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 301-747, Korea
² Department of Pathology, College of Medicine, Chungnam National University, Daejeon 301-747, Korea
³ Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon 301-747, Korea
⁴ Department of Physiology, College of Medicine, Chungnam National University, Daejeon 301-747, Korea
⁵ Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon 301-747, Korea
⁶ National Creative Research Initiatives Center for Energy Homeostasis Regulation, Seoul National University, Seoul 151-742, Korea
⁷ Glycomics Team, Korea Basic Science Institute, Daejeon 305-333, Korea
⁸ Department of Research and Development, Korean Institute of Tuberculosis, Osong Bio-Health Science Technopolis, Chungbuk 363-954, Korea
⁹ Department of Genetics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
¹⁰These authors contributed equally to this work
¹¹Present address: BioMedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea
¹²Present address: Department of Microbiology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 120-752, Korea

^*Corresponding author : Eun-Kyeong Jo

Summary
The current standard of treatment against tuberculosis consists of a cocktail of first-line drugs, including isoniazid and pyrazinamide. Although these drugs are known to be bactericidal, contribution of host cell responses in the context of antimycobacterial chemotherapy, if any, remains unknown. We demonstrate that isoniazid and pyrazinamide promote autophagy activation and phagosomal maturation in Mycobacterium tuberculosis (Mtb)-infected host cells. Treatment of Mtb-infected macrophages with isoniazid or pyrazinamide caused significant activation of cellular and mitochondrial reactive oxygen species and autophagy, which was triggered by bacterial hydroxyl radical generation. Mycobacterium marinum-infected autophagy-defective, atg7 mutant Drosophila exhibited decreased survival rates, which could not be rescued by antimycobacterial treatment, indicating that autophagy is required for effective antimycobacterial drug action in vivo. Moreover, activation of autophagy by antibiotic treatment dampened Mtb-induced proinflammatory responses in macrophages. Together, these findings underscore the importance of host autophagy in orchestrating successful antimicrobial responses to mycobacteria during chemotherapy.