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primary topic: Targeting Mycobacterium tuberculosis GAPDH elicits potent bactericidal responses by dysregulating enzyme activity, redox dynamics and iron acquisition

Targeting Mycobacterium tuberculosis GAPDH elicits potent bactericidal responses by dysregulating enzyme activity, redox dynamics and iron acquisition
type: AcademicArticle
type: Article
abstract: Mycobacterium tuberculosis (Mtb) Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is indispensable for glycolysis, it also performs several critical non-metabolic functions. In the present study, we demonstrate that CRISPRi silencing of GAPDH inhibited enzyme activity and iron acquisition via human transferrin (Tf)/lactoferrin (Lf). GAPDH silencing also enhanced reactive oxygen species (ROS) and ROS induced damage suggesting its role as a redox sensor. We then examined the impact of GAPDH inhibition in Mtb using small molecule inhibitors. Vitamin C (VC) was selected considering its potent bactericidal effects against Mtb and its inhibition of human GAPDH resulting in its efficacy against cancer cells. The GAPDH inhibitors Ethyl bromopyruvate (EBP) and Koningic acid (KA) are anti-cancer agents that target the glycolytic activity of GAPDH. In contrast, TCH346 was identified as a neuroprotective agent, wherein it targets the non-metabolic function of GAPDH induced apoptotic signalling. The effects of inhibitors, alone or in combination with VC mirrored the cellular effects of GAPDH silencing, resulting in significant anti-bacterial activity. VC induced iron mobilization which coupled with GAPDH inhibitors induced a veritable ``double whammy'' resulting in massive increase in ROS and downstream effects. The efficacy of these treatments was assessed in a murine model, confirming that VC augmented the potent anti-tubercular activity induced by EBP and TCH346. Overall, this study identifies the crucial function of Mtb GAPDH as a redox sensor and highlights the potential of targeting its pleiotropic cellular functions towards drug discovery. In addition, the efficacy of TCH346 provides an opportunity of drug-repurposing as a strategy for therapy.
date: 2026-04
volume: 247
status: peerReviewed
status: published
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository
subject: QR Microbiology

ELSEVIER SCIENCE INC
type: Organization

FREE RADICAL BIOLOGY AND MEDICINE
type: Collection

Gattadi Sravani
type: Person
given name: Gattadi
family name: Sravani

Anjali Kumari
type: Person
given name: Anjali
family name: Kumari

Vinay Kumar Yadav
type: Person
given name: Vinay Kumar
family name: Yadav

Rajender Kumar
type: Person
given name: Rajender
family name: Kumar

Pradip Malik
type: Person
given name: Pradip
family name: Malik

Nisheeth Agarwal
type: Person
given name: Nisheeth
family name: Agarwal

Asmita Dhiman
type: Person
given name: Asmita
family name: Dhiman

Mohammad Naiyaz Ahmad
type: Person
given name: Mohammad Naiyaz
family name: Ahmad

Sidharth Chopra
type: Person
given name: Sidharth
family name: Chopra

Zahid Gani
type: Person
given name: Zahid
family name: Gani

Mohmmad Imran
type: Person
given name: Mohmmad
family name: Imran

Prabha Garg
type: Person
given name: Prabha
family name: Garg

Gaddam Laxmi Priya
type: Person
given name: Gaddam Laxmi
family name: Priya

Arunava Dasgupta
type: Person
given name: Arunava
family name: Dasgupta

Ajay Kumar
type: Person
given name: Ajay
family name: Kumar

Manoj Raje
type: Person
given name: Manoj
family name: Raje

Chaaya Iyengar Raje
type: Person
given name: Chaaya Iyengar
family name: Raje

Anurag Sindhu
type: Person
given name: Anurag
family name: Sindhu

HTML Summary of #3476 Targeting Mycobacterium tuberculosis GAPDH elicits potent bactericidal responses by dysregulating enzyme activity, redox dynamics and iron acquisition
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primary topic: Targeting Mycobacterium tuberculosis GAPDH elicits potent bactericidal responses by dysregulating enzyme activity, redox dynamics and iron acquisition

QR Microbiology
type: Concept