Gani, Zahid and Ahmad, Mohammad Naiyaz and Sindhu, Anurag and Kumar, Ajay and Kumari, Anjali and Imran, Mohmmad and Malik, Pradip and Dhiman, Asmita and Yadav, Vinay Kumar and Priya, Gaddam Laxmi and Sravani, Gattadi and Agarwal, Nisheeth and Kumar, Rajender and Garg, Prabha and Dasgupta, Arunava and Chopra, Sidharth and Raje, Manoj and Raje, Chaaya Iyengar (2026) Targeting Mycobacterium tuberculosis GAPDH elicits potent bactericidal responses by dysregulating enzyme activity, redox dynamics and iron acquisition. FREE RADICAL BIOLOGY AND MEDICINE, 247. pp. 54-70.
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Additional Information: | Copyright of this article belongs to ELSEVIER SCIENCE. |
| Subjects: | Q Science > QR Microbiology |
| Depositing User: | Dr. K.P.S.Sengar |
| Date Deposited: | 09 Jul 2026 11:07 |
| Last Modified: | 09 Jul 2026 11:07 |
| URI: | http://crdd.osdd.net/open/id/eprint/3476 |
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