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

Tuberculosis (Edinb). 2018 Sep;112:98-109. doi: 10.1016/j.tube.2018.08.004. Epub 2018 Aug 11.

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 14C-uracil and 14C-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.

Keywords: Antimalarial; Gyrase; Mycobacterium tuberculosis; Pyronaridine; RNA polymerase; Repurposing; Topoisomerase; Tuberculosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antitubercular / pharmacology*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Binding Sites
  • DNA-Directed RNA Polymerases / antagonists & inhibitors*
  • DNA-Directed RNA Polymerases / chemistry
  • DNA-Directed RNA Polymerases / metabolism
  • Drug Repositioning
  • Drug Resistance, Bacterial
  • Drug Synergism
  • Drug Therapy, Combination
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Mycobacterium tuberculosis / growth & development
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology*
  • Protein Binding
  • Protein Conformation
  • Rifampin / pharmacology*
  • Structure-Activity Relationship
  • THP-1 Cells

Substances

  • Antibiotics, Antitubercular
  • Antimalarials
  • Antitubercular Agents
  • Bacterial Proteins
  • Naphthyridines
  • DNA-Directed RNA Polymerases
  • pyronaridine
  • Rifampin