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Inhibitors of acetohydroxyacid synthase as promising agents against non-tuberculous mycobacterial diseases

The Journal of Antibiotics volume 78, pages 181–189 (2025)Cite this article

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Abstract

Acetohydroxyacid synthase (AHAS), exclusively present in microorganisms and plants, is a promising target for several herbicides due to its catalytic role in the branched-chain amino acid biosynthetic pathway. Previous studies have shown that K13787, a pyrazolopyrimidine sulfonamide AHAS inhibitor, was moderately effective against pulmonary infection caused by M. tuberculosis and nontuberculous mycobacteria (NTM). In this study, we synthesized various structural derivatives of K13787 based on the molecular docking studies and assessed their MICs against mycobacteria species. Among the synthetic compounds screened, K13787, along with KNT2077 and KNT2099, exhibited inhibitory efficacy against M. avium and M. abscessus, including CLR-resistant NTM species. Notably, these compounds displayed a synergistic effect (FIC ≤ 0.5) when combined with CLR against M. avium and M. abscessus. Our findings suggest that these newly identified AHAS-targeted compounds hold promise as lead candidates for novel antimycobacterial agents against NTM infections. Considering the structure-activity relationship, K13787, KNT2077, and KTN2099 emerge as potential treatments for NTM species.

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Acknowledgements

TDN, JAC: Designed the study, Performance the majority of the experiments, Analyzed the data, Validation, Writing—original draft. H-JL, CHC: Providing the synthetics compounds and expert technical assistance. JL: Methodology, Validation. S-HS: Data curation, Methodology. JK: Methodology, Validation. DS: Investigation, Formal analysis. H-JK: Conceptualization, Supervision, Writing—review and editing. C-HS: Designed the study, Supervision, Project administration, Funding acquisition, Writing—review and editing. All named authors meet the International Committee of Medical Journal Editors criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2022R1C1C2011153). The funders had no role in study design, data collection and analysis decision to publish, or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Tam Doan Nguyen, Ji-Ae Choi

Authors and Affiliations

  1. Department of Microbiology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, South Korea

    Tam Doan Nguyen, Ji-Ae Choi, Junghwan Lee, Sang-Hun Son, Jaewhan Kim, Doyi Son, Hwa-Jung Kim & Chang-Hwa Song

  2. Department of Medical Science, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, South Korea

    Tam Doan Nguyen, Ji-Ae Choi, Junghwan Lee, Sang-Hun Son, Jaewhan Kim, Doyi Son, Hwa-Jung Kim & Chang-Hwa Song

  3. Brain Korea 21 FOUR Project for Medical Science, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, South Korea

    Ji-Ae Choi

  4. Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, South Korea

    Hee-Jong Lim & Chong Hak Chae

  5. Translational Immunology Institute, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, South Korea

    Junghwan Lee, Doyi Son, Hwa-Jung Kim & Chang-Hwa Song

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  1. Tam Doan Nguyen
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Correspondence to Hwa-Jung Kim or Chang-Hwa Song.

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The authors declare no competing interests.

Ethics

All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee of Chungnam National University (Daejeon, Korea, CNU-00907). Animal experiments were performed in accordance with Korean Food and Drug Administration guidelines.

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Nguyen, T.D., Choi, JA., Lim, HJ. et al. Inhibitors of acetohydroxyacid synthase as promising agents against non-tuberculous mycobacterial diseases. J Antibiot 78, 181–189 (2025). https://doi.org/10.1038/s41429-024-00799-z

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