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

Mori, Giorgia, Orena, Beatrice Silvia, Franch, Clara, Mitchenall, Lesley A., Godbole, Adwait Anand, Liliana Isabel Dias Rodrigues, Aguilar-Pérez, Clara, J. Zemanova, Huszár, Stanislav, Forbak, Martin, Lane, Thomas R., Sabbah, Mohamad Mohamad, Deboosère, Nathalie, Frita, Rosangela, Vandeputte, Alexandre, Hoffmann, Eik, Russo, Riccardo Riccardo, Connell, Nancy D., Veilleux, Courtney A., Kumar, Rajiv & 9 others Kumar, Pradeep Ravi, Freundlich, Joel S., Brodin, Priscille, José A. Aínsa, Nagaraja, Valakunja, Maxwell, Anthony, Mikušová, Katarína, Pasca, Maria Rosalia, Ekins, Sean

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)98-109
Number of pages12
JournalTuberculosis
VolumeVol. 112
DOIs
Publication statusPublished - Sep 2018

Fingerprint

Antimalarials
DNA-Directed RNA Polymerases
Rifampin
Mycobacterium tuberculosis
Drug Repositioning
pyronaridine
Mycobacterium Infections
Uracil
European Union
Leucine
Malaria
Macrophages
In Vitro Techniques
Infection

Keywords

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

Cite this

Giorgia, Mori, ; Beatrice Silvia, Orena, ; Clara, Franch, ; Lesley A., Mitchenall, ; Adwait Anand, Godbole, ; Rodrigues, Liliana Isabel Dias ; Clara, Aguilar-Pérez, ; Zemanova, J. ; Stanislav, Huszár, ; Martin, Forbak, ; Thomas R., Lane, ; Mohamad, Sabbah, Mohamad ; Nathalie, Deboosère, ; Rosangela, Frita, ; Alexandre, Vandeputte, ; Eik, Hoffmann, ; Riccardo, Russo, Riccardo ; Nancy D., Connell, ; Courtney A., Veilleux, ; Rajiv, Kumar, ; Pradeep Ravi, Kumar, ; Joel S., Freundlich, ; Priscille, Brodin, ; Aínsa, José A. ; Valakunja, Nagaraja, ; Anthony, Maxwell, ; Katarína, Mikušová, ; Maria Rosalia, Pasca, ; Sean, Ekins, . / The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase. In: Tuberculosis. 2018 ; Vol. Vol. 112. pp. 98-109.
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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",
author = "Mori, Giorgia and {Beatrice Silvia}, Orena, and Franch, Clara and {Lesley A.}, Mitchenall, and {Adwait Anand}, Godbole, and Rodrigues, {Liliana Isabel Dias} and Aguilar-P{\'e}rez, Clara and J. Zemanova and Husz{\'a}r, Stanislav and Forbak, Martin and {Thomas R.}, Lane, and Mohamad, {Sabbah, Mohamad} and Deboos{\`e}re, Nathalie and Frita, Rosangela and Vandeputte, Alexandre and Hoffmann, Eik and Riccardo, {Russo, Riccardo} and {Nancy D.}, Connell, and {Courtney A.}, Veilleux, and Kumar, Rajiv and {Pradeep Ravi}, Kumar, and {Joel S.}, Freundlich, and Brodin, Priscille and A{\'i}nsa, {Jos{\'e} A.} and Nagaraja, Valakunja and Maxwell, Anthony and Mikušov{\'a}, Katar{\'i}na and {Maria Rosalia}, Pasca, and Ekins, Sean",
year = "2018",
month = "9",
doi = "10.1016/j.tube.2018.08.004",
language = "English",
volume = "Vol. 112",
pages = "98--109",
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Giorgia, M, Beatrice Silvia, O, Clara, F, Lesley A., M, Adwait Anand, G, Rodrigues, LID, Clara, A-P, Zemanova, J, Stanislav, H, Martin, F, Thomas R., L, Mohamad, SM, Nathalie, D, Rosangela, F, Alexandre, V, Eik, H, Riccardo, RR, Nancy D., C, Courtney A., V, Rajiv, K, Pradeep Ravi, K, Joel S., F, Priscille, B, Aínsa, JA, Valakunja, N, Anthony, M, Katarína, M, Maria Rosalia, P & Sean, E 2018, 'The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase', Tuberculosis, vol. Vol. 112, pp. 98-109. https://doi.org/10.1016/j.tube.2018.08.004

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, ; Rodrigues, Liliana Isabel Dias; Clara, Aguilar-Pérez, ; Zemanova, J.; Stanislav, Huszár, ; Martin, Forbak,; Thomas R., Lane, ; Mohamad, Sabbah, Mohamad; Nathalie, Deboosère, ; Rosangela, Frita, ; Alexandre, Vandeputte, ; Eik, Hoffmann, ; Riccardo, Russo, Riccardo; Nancy D., Connell, ; Courtney A., Veilleux, ; Rajiv, Kumar, ; Pradeep Ravi, Kumar, ; Joel S., Freundlich, ; Priscille, Brodin, ; Aínsa, José A.; Valakunja, Nagaraja, ; Anthony, Maxwell, ; Katarína, Mikušová, ; Maria Rosalia, Pasca, ; Sean, Ekins, .

In: Tuberculosis, Vol. Vol. 112, 09.2018, p. 98-109.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase

AU - Giorgia, Mori,

AU - Beatrice Silvia, Orena,

AU - Clara, Franch,

AU - Lesley A., Mitchenall,

AU - Adwait Anand, Godbole,

AU - Rodrigues, Liliana Isabel Dias

AU - Clara, Aguilar-Pérez,

AU - Zemanova, J.

AU - Stanislav, Huszár,

AU - Martin, Forbak,

AU - Thomas R., Lane,

AU - Mohamad, Sabbah, Mohamad

AU - Nathalie, Deboosère,

AU - Rosangela, Frita,

AU - Alexandre, Vandeputte,

AU - Eik, Hoffmann,

AU - Riccardo, Russo, Riccardo

AU - Nancy D., Connell,

AU - Courtney A., Veilleux,

AU - Rajiv, Kumar,

AU - Pradeep Ravi, Kumar,

AU - Joel S., Freundlich,

AU - Priscille, Brodin,

AU - Aínsa, José A.

AU - Valakunja, Nagaraja,

AU - Anthony, Maxwell,

AU - Katarína, Mikušová,

AU - Maria Rosalia, Pasca,

AU - Sean, Ekins,

PY - 2018/9

Y1 - 2018/9

N2 - 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.

AB - 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.

KW - Antimalarial

KW - Gyrase

KW - Mycobacterium tuberculosis

KW - Pyronaridine

KW - RNA polymerase

KW - Repurposing

KW - Topoisomerase

KW - Tuberculosis

U2 - 10.1016/j.tube.2018.08.004

DO - 10.1016/j.tube.2018.08.004

M3 - Article

VL - Vol. 112

SP - 98

EP - 109

JO - Tuberculosis

JF - Tuberculosis

SN - 1472-9792

ER -