Biology subjects

Agnivesh, P. K.

Publications and source records attributed to Agnivesh, P. K..

3 recordsLinked to original sources

bioRxiv2026

Exploiting NDH-2 Vulnerability: Quinolines as Antitubercular Agents

Mycobacterium tuberculosis possesses a flexible metabolic system helping it to survive inside the host. The type II NADH dehydrogenase, composed of Ndh and NdhA, essential for bacilli, is a promising drug target. Based on ATP depletion values, two quinoline scaffolds were shortlisted after screening of a library of drug like molecules. Structurally, both 64-9C and 64-9D carry ester moieties at the 5- and 8-positions of the quinoline core, respectively. Ease to re-synthesise 64-9D resulted in synthesis of a focused library of compounds, with MIC values of 0.25-4 g/mL, consistent with ATP depletion. These compounds exhibited bactericidal activity against non-replicating mycobacteria, and showed potent efficacy against multidrug-resistant isolates. Altered, intracellular NADH/NAD+ ratio and reduced respiration was indicative of oxidative phosphorylation inhibition. Inhibition of the purified recombinant NDH protein uncompetitively, SNPs in gene encoding NDH-2 for selected one step mutants and, molecular modelling of 4FQN and 2FQN validated NDH-2 as a target for these compounds. The derivative 2FQN exhibited dose-dependent bactericidal efficacy in mice, underscoring the potential of the series as a promising anti-tuberculosis candidates.

microbiology↗

bioRxiv2025

Repurposing ethacridine as a potent MMPL3 Inhibitor for the treatment of tuberculosis

Mycobacterium tuberculosis (Mtb), the pathogen responsible for tuberculosis, remains a major global health threat, particularly with the rise of multidrug-resistant and extensively drug-resistant strains. This has renewed interest in repurposing existing drugs and exploring new cellular targets. The mycobacterial cell envelope is a key barrier to antibiotics and an attractive site for therapeutic intervention. In this study, we identify the FDA-approved drug ethacridine as a strong inhibitor of MmpL3, an essential transporter required for exporting trehalose monomycolate and building the cell wall. Computational docking and molecular dynamics indicate that ethacridine engages the MmpL3 binding pocket at residues also targeted by SQ109. Ethacridine shows potent activity against drug-sensitive and resistant Mtb isolates, with an MIC of 1 g/mL, and remains effective against non-replicating bacteria and intracellular infection. Ethacridine-resistant mutants, overexpression strains, and a spheroplast TMM-flipping assay confirm MmpL3 as the target. The compound also disrupts the membrane potential, and flow-cytometry assays

microbiology↗

bioRxiv2025

Targeting Metabolic Vulnerabilities: Valinomycin Augments the Potency of Bioenergetic Inhibitors in Combatting Drug-Resistant and Dormant Mycobacterium tuberculosis

Tuberculosis (TB) treatment is hampered by monotherapy limitations and phenotypic drug tolerance, citing the need for effective drug combinations. The mycobacterial electron transport chain (ETC), crucial for oxidative phosphorylation and ATP production in dormant Mycobacterium tuberculosis (Mtb), is a key target. This study investigates combining established bioenergetic inhibitors-bedaquiline (BDQ), telacebec (Q203), and clofazimine (CFZ) with the potassium ionophore valinomycin, which disrupts the proton motive force (pmf). We demonstrated that valinomycin significantly potentiated the anti-TB activity of these inhibitors against both replicating and nutrient-starved non-replicating Mtb. Checkerboard assays revealed synergistic activity with BDQ and additive effects with Q203 and CFZ, correlated with a two to three-fold reduction in ATP IC50 values. Critically, valinomycin converted the bacteriostatic activity of the inhibitors at sub-MIC concentration into bactericidal killing in time-dependent killing assay, achieving sterilization. This lethal synergy for the combinations was also observed in a THP-1 macrophage intracellular model for TB. Respiration assays confirmed that the combinations collectively halted oxygen consumption. We conclude that concurrently targeting specific ETC on Mtbs bioenergetics. This strategy, particularly the BDQ/valinomycin synergy, represents a promising cornerstone for developing novel sterilizing regimens to shorten TB therapy and overcoming drug tolerance.

microbiology↗