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+, pH, Cl- and K+.

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 cipargamin, 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

  • Rosling, J.E.O., Ridgway, M.C., Summers, R.L., Kirk, K. and Lehane, A.M. (2018) Biochemical characterization and chemical inhibition of PfATP4-associated Na+-ATPase activity in Plasmodium falciparum membranes. J. Biol. Chem., In Press.
     
    Dennis, A.S.M., Rosling, J.E.O., Lehane, A.M. and Kirk, K. (2018) Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis. Sci. Rep. 8, 8795.
     
    Dennis, A.S.M., Lehane, A.M., Ridgway, M.C., Holleran, J. and Kirk, K. (2018) Cell swelling induced by the antimalarial KAE609 (cipargamin) and other PfATP4-associated antimalarials.  Antimicrob. Agents Chemother. 62, e00087-18.
     
    Hapuarachchi, S.V., Cobbold, S.A., Shafik, S.H., Dennis, A.S.M., McConville, M.J., Martin, R.E., Kirk, K. and Lehane, A.M. (2017) The malaria parasite's lactate transporter PfFNT is the target of antiplasmodial compounds identified in whole cell phenotypic screens. PLoS Pathogens, 13, e1006180.
     
    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.
     
    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.
     
    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 Pathogens 12, e1005763.
     
    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. and 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:  22 September 2018/Responsible Officer:  Director RSB/Page Contact:  Webmaster RSB