Disruption of De Novo Histidine Biosynthesis of <i>Mycobacterium tuberculosis</i> Affects the Depletion of the Pathogen

<i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), the causative agent of human tuberculosis (TB), employs its de novo histidine (His) biosynthesis to escape host-inflicted His starvation. This makes the enzymes involved in this biosynthetic pathway promising anti-TB drug targets. In this study, employing the high-resolution crystal structure of imidazole glycerol phosphate dehydratase (IGPD) of the <i>Mtb</i> His pathway, three triazole scaffold molecules were identified as potential inhibitors of this enzyme. These high-resolution crystal structures of the enzyme-inhibitor complexes elucidated the key interactions responsible for their binding specificity and affinity. We also studied the interactions of these inhibitors with the enzyme at the atomic level and tested their cytotoxicity and efficacy in <i>in vitro</i> and <i>in vivo</i> models. Our findings revealed that the most prominent inhibitor, SF2, was safe in mice and effectively inhibited the <i>in vitro</i> growth of both free as well as in macrophage-internalized wild-type and drug-resistant <i>Mtb</i> clinical isolates. Notably, SF2 also showed a marginal reduction in the bacterial load in organs of mice infected with <i>Mtb</i>. Collectively, these findings advocate the chemical inhibition of IGPD of the His pathway as a novel anti-<i>Mtb</i> therapeutic strategy.

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Journal
ACS Infectious Diseases
Published
2025-11-24
DOI
https://doi.org/10.1021/acsinfecdis.5c00393
Primary Topic
Enzyme Structure and Function
Type
article
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article

Disruption of De Novo Histidine Biosynthesis of Mycobacterium tuberculosis Affects the Depletion of the Pathogen

Soumya Banerjee, Amit Kumar Pandey, Rahul Pal, Ranjan Kumar Nanda et al.
ACS Infectious Diseases
Enzyme Structure and Function
article

Disruption of De Novo Histidine Biosynthesis of Mycobacterium tuberculosis Affects the Depletion of the Pathogen

Soumya Banerjee, Amit Kumar Pandey, Rahul Pal, Ranjan Kumar Nanda, Yashwant Kumar, Jaswinder Singh Maras, Amit Kumar Mohapatra, Abhisek Dwivedy, Vaibhav Kumar Nain, Deepsikha Kar, Manish Kumar Bajpai, Mohammed Ahmad, B.K. Biswal, Neha Sharma, Perumal Nagarajan, Vishawjeet Barik, Swati Kumari, Ravi Kant Pal, Varun Kumar, Satish Tiwari, Mohini Singla
article en

Abstract

<i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), the causative agent of human tuberculosis (TB), employs its de novo histidine (His) biosynthesis to escape host-inflicted His starvation. This makes the enzymes involved in this biosynthetic pathway promising anti-TB drug targets. In this study, employing the high-resolution crystal structure of imidazole glycerol phosphate dehydratase (IGPD) of the <i>Mtb</i> His pathway, three triazole scaffold molecules were identified as potential inhibitors of this enzyme. These high-resolution crystal structures of the enzyme-inhibitor complexes elucidated the key interactions responsible for their binding specificity and affinity. We also studied the interactions of these inhibitors with the enzyme at the atomic level and tested their cytotoxicity and efficacy in <i>in vitro</i> and <i>in vivo</i> models. Our findings revealed that the most prominent inhibitor, SF2, was safe in mice and effectively inhibited the <i>in vitro</i> growth of both free as well as in macrophage-internalized wild-type and drug-resistant <i>Mtb</i> clinical isolates. Notably, SF2 also showed a marginal reduction in the bacterial load in organs of mice infected with <i>Mtb</i>. Collectively, these findings advocate the chemical inhibition of IGPD of the His pathway as a novel anti-<i>Mtb</i> therapeutic strategy.

ACS Infectious DiseasesVol. 11(12)
Translational Health Science and Technology Institute (IN), Institute of Liver and Biliary Sciences (IN), International Centre for Genetic Engineering and Biotechnology (IN), National Institute of Immunology (IN)
Openalex Percentile: Top 71%
Enzyme Structure and Function
DOISourceOpenAlex
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