TY  - JOUR
CY  - STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA
N1  - Copyright of this article belongs to ELSEVIER SCIENCE.
ID  - open3476
UR  - http://crdd.osdd.net/open/3476/
A1  - Gani, Zahid
A1  - Ahmad, Mohammad Naiyaz
A1  - Sindhu, Anurag
A1  - Kumar, Ajay
A1  - Kumari, Anjali
A1  - Imran, Mohmmad
A1  - Malik, Pradip
A1  - Dhiman, Asmita
A1  - Yadav, Vinay Kumar
A1  - Priya, Gaddam Laxmi
A1  - Sravani, Gattadi
A1  - Agarwal, Nisheeth
A1  - Kumar, Rajender
A1  - Garg, Prabha
A1  - Dasgupta, Arunava
A1  - Chopra, Sidharth
A1  - Raje, Manoj
A1  - Raje, Chaaya Iyengar
Y1  - 2026/04//
N2  - 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.
PB  - ELSEVIER SCIENCE INC
JF  - FREE RADICAL BIOLOGY AND MEDICINE
VL  - 247
TI  - Targeting Mycobacterium tuberculosis GAPDH elicits potent bactericidal responses by dysregulating enzyme activity, redox dynamics and iron acquisition
SP  - 54
EP  - 70
ER  -