Revitalizing antimicrobial strategies: paromomycin and dicoumarol repurposed as potent inhibitors of M.tb's replication machinery via targeting the vital protein DnaN

• Published in: International journal of biological macromolecules Vol. 278; no. Pt 3; p. 134652
• Main Authors: Ali, Waseem, Agarwal, Meetu, Jamal, Salma, Gangwar, Rishabh, Sharma, Rahul, Mubarak, Mohamad Mosa, Wani, Zubair Ahmad, Ahmad, Zahoor, Khan, Areeba, Sheikh, Javaid Ahmad, Grover, Abhinav, Bhaskar, Ashima, Dwivedi, Ved Prakash, Grover, Sonam
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-10-2024
• Subjects: Anti-mycobacterial compound; M.tb DnaN; Molecular dynamics simulations; M.tb DnaN; Anti-mycobacterial compound; Molecular dynamics simulations
• ISSN: 0141-8130; 1879-0003; 1879-0003
• DOI: 10.1016/j.ijbiomac.2024.134652

Despite the WHO's recommended treatment regimen, challenges such as patient non-adherence and the emergence of drug-resistant strains persist with TB claiming 1.5 million lives annually. In this study, we propose a novel approach by targeting the DNA replication-machinery of M.tb through drug-repurposing. The β2-Sliding clamp (DnaN), a key component of this complex, emerges as a potentially vulnerable target due to its distinct structure and lack of human homology. Leveraging TBVS, we screened ∼2600 FDA-approved drugs, identifying five potential DnaN inhibitors, by employing computational studies, including molecular-docking and molecular-dynamics simulations. The shortlisted compounds were subjected to in-vitro and ex-vivo studies, evaluating their anti-mycobacterial potential. Notably, Dicoumarol, Paromomycin, and Posaconazole exhibited anti-TB properties with a MIC value of 6.25, 3.12 and 50 μg/ml respectively, with Dicoumarol and Paromomycin, demonstrating efficacy in reducing live M.tb within macrophages. Biophysical analyses confirmed the strong binding-affinity of DnaNdrug complexes, validating our in-silico predictions. Moreover, RNA-Seq data revealed the upregulation of proteins associated with DNA repair and replication mechanisms upon Paromomycin treatment.
This study explores repurposing FDA-approved drugs to target TB via the mycobacterial DNA replication-machinery, showing promising inhibitory effects. It sets the stage for further clinical research, demonstrating the potential of drug repurposing in TB treatment.