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Evaluation of a novel inhibitor of aspartate semialdehyde dehydrogenase as a potent antitubercular agent against Mycobacterium tuberculosis

The Journal of Antibiotics volume 75, pages 333–340 (2022)Cite this article

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Abstract

The in vitro activity of IMB-XMA0038, a novel inhibitor targeting Mycobacterial tuberculosis (Mtb) aspartate semialdehyde dehydrogenase, was evaluated. Minimum inhibitory concentrations (MICs) of IMB-XMA0038 were against 20 Mtb isolates, including H37Rv (ATCC 27294), ten clinical pan-sensitive isolates, and nine clinical multidrug-resistant (MDR) isolates. In addition, minimum bactericidal concentrations (MBCs) were also determined against the H37Rv and 6 MDR isolates (the background information is same as above in order). A model was generated to evaluate IMB-XMA0038 activity against dormant Mtb. The post-antibiotic effect (PAE), an important indicator of antimicrobial drug dosing schedules to obtain efficacy, was determined based on time required for regrowth of Mtb to 50% of the OD600max value after treatment with various concentrations of IMB-XMA0038 and INH. In addition, interactions between IMB-XMA0038 and other anti-tuberculosis drugs, measured using a checkerboard assay, revealed that IMB-XMA0038 MICs of 0.5–1 μg/mL could be achieved in combinations. Synergistic effects were observed for IMB-XMA0038 when used together with almost all other anti-tuberculosis drugs against most Mtb isolates. IMB-XMA0038 exhibited greater activity than rifampin against Mtb under hypoxic conditions, as reflected by CFU decreases of 1.1-log-unit versus 0.8-log-unit, respectively, for IMB-XMA0038 and rifampin concentrations of 4 × MIC. IMB-XMA0038-induced PAEs (9, 10, 11 days) were comparable to INH PAEs (10, 11, 12 days). These findings suggest that addition of IMB-XMA0038 to current therapeutic regimens could be useful to improve the efficacy of treatments for drug-resistant and drug-susceptible TB.

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Acknowledgements

We thank the study coordinators and staff at the hospital for their contributions to this research. This study was supported by Natural Sciences Foundation of China (NSFC, Grant No. 81803412), and the Beijing Key Clinical Specialty Project.

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Authors and Affiliations

  1. Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University / Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China

    Ruifang Yang, Qiao Li, Chen Liang, Weicong Ren, Yi Liu & Chuanyou Li

  2. Department of Respiratory and Critical Care Medicine, Beijing Geriatric Hospital, Beijing, 100095, China

    Wenli Cao

  3. Department of Tuberculosis, Anhui Chest Hospital, Hefei, Anhui, 230022, China

    Shengsheng Liu

  4. Department of Clinical Laboratory, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China

    Yong Sun

  5. Institute of Medical Biotechnology, Chinese Academy of Medical Sciences, Beijing, 100050, China

    Jianzhou Meng

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  1. Ruifang Yang
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Yang, R., Cao, W., Liu, S. et al. Evaluation of a novel inhibitor of aspartate semialdehyde dehydrogenase as a potent antitubercular agent against Mycobacterium tuberculosis. J Antibiot 75, 333–340 (2022). https://doi.org/10.1038/s41429-022-00520-y

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