Ohmyungsamycin promotes M1-like inflammatory responses to enhance host defence against Mycobacteroides abscessus infections

• Published in: Virulence Vol. 13; no. 1; pp. 1966 - 1984
• Main Authors: Jeon, Sang Min, Kim, Young Jae, Nguyen, Thanh Quang, Cui, Jinsheng, Thi Bich Hanh, Bui, Silwal, Prashanta, Kim, Jin Kyung, Kim, Jin-Man, Oh, Dong-Chan, Jang, Jichan, Jo, Eun-Kyeong
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 31.12.2022; Taylor & Francis Group
• Subjects: Animals; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Humans; innate immunity; M1 macrophage responses; Macrophages - microbiology; Mice; mitochondrial reactive oxygen species; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous - metabolism; Mycobacteroides abscessus; nitric oxide; Ohmyungsamycins; Research Paper; Zebrafish; nitric oxide; M1 macrophage responses; innate immunity; mitochondrial reactive oxygen species; Mycobacteroides abscessus; Ohmyungsamycins
• ISSN: 2150-5594; 2150-5608
• DOI: 10.1080/21505594.2022.2138009

Ohmyungsamycin A (OMS) is a newly identified cyclic peptide that exerts antimicrobial effects against Mycobacterium tuberculosis. However, its role in nontuberculous mycobacteria (NTMs) infections has not been clarified. Mycobacteroides abscessus (Mabc) is a rapidly growing NTM that has emerged as a human pathogen in both immunocompetent and immunosuppressed individuals. In this study, we demonstrated that OMS had significant antimicrobial effects against Mabc infection in both immunocompetent and immunodeficient mice, and in macrophages. OMS treatment amplified Mabc-induced expression of M1-related proinflammatory cytokines and inducible nitric oxide synthase, and significantly downregulated arginase-1 expression in murine macrophages. In addition, OMS augmented Mabc-mediated production of mitochondrial reactive oxygen species (mtROS), which promoted M1-like proinflammatory responses in Mabc-infected macrophages. OMS-induced production of mtROS and nitric oxide was critical for OMS-mediated antimicrobial responses during Mabc infections. Notably, the combination of OMS and rifabutin had a synergistic effect on the antimicrobial responses against Mabc infections in vitro, in murine macrophages, and in zebrafish models in vivo. Collectively, these data strongly suggest that OMS may be an effective M1-like adjunctive therapeutic against Mabc infections, either alone or in combination with antibiotics.