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

Giorgia Mori, Beatrice Silvia Orena, Clara Franch, Lesley A. Mitchenall, Adwait Anand Godbole, Liliana Rodrigues, Clara Aguilar-Pérez, Júlia Zemanová, Stanislav Huszár, Martin Forbak, Thomas R. Lane, Mohamad Sabbah, Nathalie Deboosere, Rosangela Frita, Alexandre Vandeputte, Eik Hoffmann, Riccardo Russo, Nancy Connell, Courtney Veilleux, Rajiv KumarPradeep Kumar, Joel S. Freundlich, Priscille Brodin, Jose Antonio Aínsa, Valakunja Nagaraja, Anthony Maxwell, Katarína Mikušová, Maria Rosalia Pasca, Sean Ekins

Research output: Contribution to journalArticlepeer-review

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 μg/mL). In macromolecular synthesis assays, pyronaridine resulted in a severe decrease in incorporation of 14 C-uracil and 14 C-leucine similar to the effect of rifampicin, a known inhibitor of M. tuberculosis RNA polymerase. Surprisingly, the co-administration of pyronaridine (2.5 μg/ml) and rifampicin resulted in in vitro synergy with an MIC 0.0019–0.0009 μg/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.

Original languageEnglish (US)
Pages (from-to)98-109
Number of pages12
JournalTuberculosis
Volume112
DOIs
StatePublished - Sep 2018

Keywords

  • Antimalarial
  • Gyrase
  • Mycobacterium tuberculosis
  • Pyronaridine
  • RNA polymerase
  • Repurposing
  • Topoisomerase
  • Tuberculosis

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

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