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

ABSTRACT

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.

KEYWORDS:

• Ohmyungsamycins
• Mycobacteroides abscessus
• M1 macrophage responses
• mitochondrial reactive oxygen species
• nitric oxide
• innate immunity

Acknowledgements

We thank to Dr. Laurent Kremer (CNRS, IRIM, Universite’ de Montpellier, Montpellier, France) for kindly providing Mab subsp. abscessus CIP 104536T S and R morphotypes. We thank Dr. H.W. Suh, and Dr. E.J. Park (Chungnam National University) for excellent technical assistance and E-KJ’s lab members for their critical discussions.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability

The data that support the findings of this study are available from the corresponding authors, Eun-Kyeong Jo, Jichan Jang, and Dong-Chan Oh upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21505594.2022.2138009

Additional information

Funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2017R1A5A2015385) at Chungnam National University and (No. 2020R1A2C1004077) at Gyeongsang National University, (No. 2020R1A2C2003518) at Seoul National University, and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HI22C1361).