Revitalizing antimicrobial strategies: paromomycin and dicoumarol repurposed as potent inhibitors of M.tb's replication machinery via targeting the vital protein DnaN.
Int J Biol Macromol
; : 134652, 2024 Aug 20.
Article
em En
| MEDLINE
| ID: mdl-39173789
ABSTRACT
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 ß2-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⯵g/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.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Int J Biol Macromol
Ano de publicação:
2024
Tipo de documento:
Article