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The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase

Mori, Giorgia and Orena, Beatrice Silvia and Franch, Clara and Mitchenall, Lesley A and Godbole, Adwait Anand and Rodrigues, Liliana and Aguilar-Perez, Clara and Zemanova, Julia and Huszar, Stanislav and Forbak, Martin and Lane, Thomas R and Sabbah, Mohamad and Deboosere, Nathalie and Frita, Rosangela and Vandeputte, Alexandre and Hoffmann, Eik and Russo, Riccardo and Connel, Nancy and Veilleux, Courtney and Jha, Rajiv K and Kumar, Pradeep and Freundlich, Joel S and Brodin, Priscille and Ainsa, Jose Antonio and Nagaraja, Valakunja and Maxwell, Anthony and Mikusova, Katarina and Pasca, Maria Rosalia and Ekins, Sean (2018) The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase. In: TUBERCULOSIS, 112 . pp. 98-109.

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Official URL: http://dx.doi.org/10.1016/j.tube.2018.08.004

Abstract

The search for compounds with biological activity for many diseases is turning increasingly to drug repurposing. In this study, we have focused on the European Union-approved antimalarial pyronaridine which was found to have in vitro activity against Mycobacterium tuberculosis (MIC 5 mu g/mL). In macromolecular synthesis assays, pyronaridine resulted in a severe decrease in incorporation of C-14-uracil and C-14-leucine similar to the effect of rifampicin, a known inhibitor of M. tuberculosis RNA polymerase. Surprisingly, the co-administration of pyronaridine (2.5 mu g/ml) and rifampicin resulted in in vitro synergy with an MIC 0.0019-0.0009 mu g/mL. This was mirrored in a THP-1 macrophage infection model, with a 16-fold MIC reduction for rifampicin when the two compounds were co-administered versus rifampicin alone. Docking pyronaridine in M. tuberculosis RNA polymerase suggested the potential for it to bind outside of the RNA polymerase rifampicin binding pocket. Pyronaridine was also found to have activity against a M. tuberculosis clinical isolate resistant to rifampicin, and when combined with rifampicin (10% MIC) was able to inhibit M. tuberculosis RNA polymerase in vitro. All these findings, and in particular the synergistic behavior with the antitubercular rifampicin, inhibition of RNA polymerase in combination in vitro and its current use as a treatment for malaria, may suggest that pyronaridine could also be used as an adjunct for treatment against M. tuberculosis infection. Future studies will test potential for in vivo synergy, clinical utility and attempt to develop pyronaridine analogs with improved potency against M. tuberculosis RNA polymerase when combined with rifampicin.

Item Type: Journal Article
Additional Information: Copy right for this article belong to CHURCHILL LIVINGSTONE, JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND
Keywords: Antimalarial; Gyrase; Mycobacterium tuberculosis; Pyronaridine; Repurposing; Topoisomerase; Tuberculosis; RNA polymerase
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Depositing User: Id for Latest eprints
Date Deposited: 27 Sep 2018 14:48
Last Modified: 27 Sep 2018 14:48
URI: http://eprints.iisc.ac.in/id/eprint/60743

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