Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug
The search for new anti-tubercular agents is vital for the fight against <i>Mycobacterium tuberculosis</i>, particularly given the rise of drug-resistant strains. DRILS-1398, a pyrazolo[4,3-<i>d</i>]pyrimidine derivative, was discovered as a potent inhibitor of <i>M.tb</i> chorismate mutase (<i>M.tb</i>-CM) with an IC<sub>50</sub> = 3.0 ± 0.2 <i>μ</i>M (<i>n</i> = 3) and IC<sub>90</sub> = 10 <i>μ</i>M. The compound demonstrated efficacy against multi-drug resistant <i>M.tb</i> strains (MIC = 4 μg/mL, ∼10.0 μM) and effective inhibition of intracellular <i>M.tb</i> in THP-1 macrophages. With favorable pharmacokinetics, moderate stability <i>in vitro</i>, and a promising safety profile, DRILS-1398 showed no toxicity at doses up to 500 mg/kg b.w./day when dosed orally daily once for 7 consecutive days in mice. Both DRILS-1398 and its formulation DRILS-1398(F) were successful in clearing <i>M.tb</i> infection from the lungs and spleen in murine models. These findings suggest DRILS-1398 as a promising lead candidate for developing a first-in-class anti-tubercular drug.
Authors
- Seyed E. Hasnain (ORCID: https://orcid.org/0000-0002-2967-0791)
- Gopalakrishnan Bulusu (ORCID: https://orcid.org/0000-0002-4958-7573)
- Nasreen Z. Ehtesham (ORCID: https://orcid.org/0000-0003-0557-0152)
- Srinivas Oruganti (ORCID: https://orcid.org/0000-0001-7111-904X)
- Fouzia Siraj (ORCID: https://orcid.org/0000-0001-7643-7936)
- Rebecca Kristina Edwin
- Manojit Pal (ORCID: https://orcid.org/0000-0001-7659-1239)
- K. Shiva Kumar (ORCID: https://orcid.org/0000-0002-1914-5037)
- Sandipan Chakraborty (ORCID: https://orcid.org/0000-0001-8759-1074)
- Parimal Misra (ORCID: https://orcid.org/0000-0003-1613-7549)
- Lakshyaveer Singh (ORCID: https://orcid.org/0000-0002-8136-6498)
- Gautham G. Shenoy (ORCID: https://orcid.org/0000-0002-1312-6257)
- Mansi Agarwal (ORCID: https://orcid.org/0000-0002-0367-7733)
- Anwar Alam (ORCID: https://orcid.org/0009-0002-0383-8450)
- Dhiraj Kumar (ORCID: https://orcid.org/0000-0002-7243-2959)
- Deepesh Biswas (ORCID: https://orcid.org/0009-0008-1164-5038)
- Farhan Jalees Ahmad
Institutions
- Safdarjang Hospital (IN)
- Manipal Academy of Higher Education (IN)
- Jamia Hamdard (IN)
- University of Hyderabad (IN)
- Indian Council of Medical Research (IN)
- Institute of Life Sciences (IN)
- International Centre for Genetic Engineering and Biotechnology (IN)
- New Delhi Tuberculosis Center (IN)
- Indian Institute of Technology Delhi (IN)
- Sharda University (IN)
Publication Details
- Journal
- iScience
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1016/j.isci.2025.112537
- Citations
- 2
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 2.79
Funders
- Department of Biotechnology, Ministry of Science and Technology, India
- Department of Science and Technology, Ministry of Science and Technology, India