Targeting ion transport in apicomplexan parasites with new generation antimalarials

Description

The intracellular malaria maintains a tight control over its internal ion concentrations while, at the same time, inducing substantial changes in the ion concentration of its host red blood cell. Current work in the lab focuses on understanding the mechanisms by which the intracellular parasite regulates its internal Na+ (Adele Lehane, Adelaide Dennis, James Rosling) and K+ (Richard Allen).

Recent work in the lab has implicated a particular membrane ion pump, 'ATP4', in the control of the parasite's internal Na+ level.  It has also led to the hypothesis that this pump is a target of a range of potential new generation antimalarials, one of which, a drug called KAE609, is in advanced clinical trials. We are investigating ATP4, both in the malaria parasite and, in collaboration with Giel van Dooren, in the related human parasite, Toxoplasma gondii.  We are also working with the Swiss-based Medicines for Malaria Venture and the Open Source Malaria Project, using 'ion assays' developed in the lab to screen potential antimalarial drug candidates. 

Students interested in working on this research project should contact Dr Adele Lehane.

Recent papers on ion regulation in the malaria parasite

  • Winterberg, M. and Kirk, K. (2016) A high-sensitivity HPLC assay for measuring intracellular Na+ and K+ and its application to Plasmodium falciparum infected erythrocytes. Sci. Rep. 6, 29241; doi: 10.1038/srep29241
     
    Williamson, A.E., Ylioja, P.M., Robertson, M.N., Antonova-Koch, Y., Avery, V., Baell, J., Batchu, H., Batra, S., Burrows,J.N., Bhattacharyya, S., Calderon, F., Charman, S.A., Clark, J., Crespo, B., Dean, M., Debbert, S.L., Delves, M., Dennis, A.S.M., Deroose, F., Duffy, S., Fletcher, S., Giaever, G., Hallyburton, I., Gamo, F-J., Gebbia, M., Guy, R,K., Hungerford, Z., Kirk, K., Lafuente-Monasterio, M.J., Lee, A., Meister, S., Nislow, C., Overington, J.P., Papadatos, G., Patiny, L., Pham, J., Ralph, S., Andrea Ruecker, A., Ryan, E., Southan, C., Srivastava, K., Swain, C., Tarnowski, M.J., Thomson, P., Turner, P., Wallace, I.M., Wells, T.N.C., White, K., White, L., Willis, P., Winzeler, E.A., Wittlin, S. and Todd, M.H. (2016) Open source drug discovery - Highly potent antimalarial compounds derived from the Tres Cantos arylpyrroles.  ACS Central Science4, e06416. doi: 10.7554/eLife.06416
     
    Van Voorhis, W.C. … Kirk, K. … Lehane A.M. … [188 authors in total] (2016) Open source drug discovery with the Malaria Box compound collection for neglected diseases and beyond. PLoS Pathog 12: e1005763. doi:10.1371/journal.ppat.1005763
     
    Kirk, K. (2015) Ion regulation in the malaria parasite. Annu. Rev. Microbiol. 69, 341–59
     
    Spillman, N.J. and Kirk, K. (2015) The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs. Int.J. Parasitol.: Drugs and Drug Resistance. 5, 149-162
     
    Jiménez-Díaz, M.B., Ebert, D., Salinas, Y., Pradhan, A., Lehane, A.M., Myrand-Lapierre, M., O’Loughlin, K.G., Shackleford, D.M., de Almeida, M.J.L., Carillo, A., Clark, J., Dennis, A.S.M., Diep, J., Deng, X., Duffy, S., Endsley, A.N., Guiguemde, G.F.A., Gomez-Lorenzo, M.G., Holbrook, G., Horst, J., Kim, C., Liu, J., Lee, M.C.S., Matheny, A., Martínez, M.S., Miller, G., Rodriguez-Alejandre, A., Sanz, L., Sigal, M., Spillman, N.J., Stein, P.D., Wang, Z., Zhu, F.,, Waterson, D., Knapp, S., Shelat, A.A., Fidock, D.A., Gamo, F.J., Charman, S.A., Mirsalis, J.C., Ma, H., Ferrer, S., Kirk, K., Angulo-Barturen, I., Kyle, D.E., DeRisi, J.L., Floyd, D.M., Guy, R.K. (2014) (+)-SJ733: A clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. Proc. Natl Acad. Sci. USA. 111, E5455- E5462
     
    Vaidya, A.B., Morrisey , J.M., Zhang, Z., Das, S., Daly, T.M., Otto, T.D., Spillman, N.J., Wyvratt, M., Siegl, P., Marfurt, J., Wirjanata, G., Sebayang, B., Price, R.N., Chatterjee, A., Nagle, A., Stasiak, M., Charman, S.A., Angulo-Barturen, I., Ferrer, S., Jiménez-Díaz, M.B., Martínez, M.S., Gamo, F.J., Avery, V.M., Ruecker, A., Delves, M., Kirk, K., Berriman, M., Kortagere, S., Burrows, J., Fan, E. and Bergman, L.W. (2014) Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum.  Nature Comm.  5, 5521
     
    Lehane, A.M., Ridgway, M.C., Baker, E., Kirk, K. (2014) Diverse chemotypes disrupt ion homeostasis in the malaria parasite. Molec. Microbiol. 94, 327-339
  • Kirk, K. and Lehane, A.L. (2014) Membrane transport in the malaria parasite and its host erythrocyte.  Biochem. J.  457, 1-18
  • Spillman, N.J., Allen, R.J.W. and Kirk, K. (2013) Na+ extrusion imposes an acid load on the intraerythrocytic malaria parasite. Mol. Biochem. Parasitol. 1891-4.
  • Spillman, N.J., Allen, R.J.W., McNamara, C.W., Yeung, B.K.S., Winzeler, E.A., Diagana, T.T. and Kirk, K. (2013) Na+ regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host & Microbe 13, 227-237.
  • van Schalkwyk, D.A., Saliba, K.J., Biagini, G.A., Bray, P.G. and Kirk, K. (2013) Loss of pH control in Plasmodium falciparum parasites subjected to oxidative stress. PLoS ONE 8, e58933.
  • Henry, R.I., Cobbold, S.A., Allen, R.J.W., Khan, A., Hayward, R., Lehane, A.M., Bray, P.G., Howitt, S.M., Biagini, G.A., Saliba, K.J., Kirk, K. (2010) An acid-loading chloride transport pathway in the intraerythrocytic malaria parasite, Plasmodium falciparum. J. Biol. Chem. 285, 18615-26.
  • Spillman, N.J., Allen, R.J.W. and Kirk, K. (2008) Acid extrusion from the intraerythrocytic malaria parasite is not via a Na+/H+ exchanger. Mol. Biochem. Parasitol. 162, 96-9

Updated:  24 November 2017/Responsible Officer:  Director RSB/Page Contact:  Webmaster RSB