Department of Microbiology & Immunology

Columbia University in the City of New York
David A. Fidock, Ph.D.
Professor of Microbiology & Immunology and Medical Sciences (in Medicine)
Ph.D., Pasteur Institute Paris

Malaria drug resistance, chemotherapy, pathogenesis, fatty acid metabolism, cell development

Research
Biological investigations into Plasmodium falciparum, the etiologic agent of severe malaria, reveal an organism that is tremendously adept at overcoming therapeutic attack and evading host immunity. This haploid apicomplexan parasite causes disease in over half a billion individuals and kills over a million African children yearly, and prevents sterilizing immunity from being acquired even by individuals who have been infected thousands of times. Disease can result from severe anemia, hyperparasitemia, or other complications resulting from sequestration of parasitized red blood cells (RBC) in the microvasculature, a process that depends on the presentation of antigenically distinct parasite proteins on the infected RBC surface. Chemotherapeutic clearance of asexual blood stage parasites is the linchpin of malaria treatment and control, however it is systematically thwarted by the acquisition of resistance. The most dramatic consequence has been with chloroquine (CQ), for decades the gold standard until resistance appeared and pre-empted a dramatic increase in malaria mortality and morbidity rates, particularly in Africa.

During my past 20 years of malaria research, I have investigated how P. falciparum invades and develops within hepatocytes and RBC, what immune effector mechanisms operate on these stages, how antimalarials act and how parasites counter their action, and how parasites are successfully transmitted to Anopheles mosquitoes, their definitive host. My laboratory's ongoing and planned research channels these interests into several themes:

1) What are the parasite factors that mediate resistance to antimalarial drugs;
2) What biological processes are targeted by antimalarial drugs and what accounts for parasite death;
3) What biochemical and physiological functions are intrinsic to the digestive vacuole (DV) and the apicoplast, the site of action of CQ and of antibiotics respectively; and
4) How does P. falciparum regulate its virulence and prevent the establishment of protective immunity.

These studies benefit from our extensive experience in P. falciparum transfection and we constantly strive for new innovations in genetics to enhance the power of these investigations.

Please see our lab website for more information about our research and publications.

Selected Publications

  1. Lee, A.H., Symington, L.S. and Fidock, D.A. (2014) DNA repair mechanisms and their biological roles in the malaria parasite Plasmodium falciparum. Microbiol. Mol. Biol. Rev. 78: 469-486.
  2. Lisewski, A.M., Quiros, J.P., Ng, C.L., Adikesavan, A.K., Miura, K., Putluri, N., Eastman, R.T., Scanfeld, D., Regenbogen, S.J., Altenhofen, L., Llinas, M., Sreekumar, A., Long, C., Fidock, D.A. and Lichtarge, O. (2014) Supergenomic network compression and the discovery of EXP1 as a glutathione transferase inhibited by artesunate. Cell 158: 916-928.
  3. Moraes Barros, R.R., Straimer, J., Sa, J.M., Salzman, R.E., Melendez-Muniz, V.A., Mu, J., Fidock, D.A.* and Wellems, T.E.* (2014) Editing the Plasmodium vivax genome, using zinc-finger nucleases. J. Infect. Dis. (in press). *Co-corresponding
  4. Kumpornsin, K., Modchang, C., Heinberg, A., Ekland, E.H., Jirawatcharadech, P., Chobson, P., Suwanakitti, N., Chaotheing, S., Wilairat, P., Deitsch, K.W., Kamchonwongpaisan, S., Fidock, D.A., Kirkman, L.A., Yuthavong, Y. and Chookajorn, T. (2014) Origin of robustness in generating drug-resistant malaria parasites. Mol. Biol. Evol. 31: 1649-1660.
  5. Johnston, G.L., Gething, P.W., Hay, S.I., Smith, D.L. and Fidock, D.A. (2014) Modeling within-host effects of drugs on Plasmodium falciparum transmission and prospects for malaria elimination. PLoS Comput. Biol. 10: e1003434.
  6. McNamara,* C.W., Lee,* M.C., Lim, C.S., Lim, S.H., Roland, J., Simon, O., Yeung, B.K.S., Chatterjee, A.K., McCormack, S.L., Manary, M.J., Zeeman, A.-M., Dechering, K.J., Kumar, T.R., Henrich, P.P., Gagaring, K., Ibanez, M., Kato, N., Kuhen, K.L., Fischli, C., Nagle, C., Rottmann, M., Plouffe, D.M., Bursulaya, B., Meister, S., Rameh, L., Trappe, J., Haasen, D., Timmerman, M., Sauerwein, R.W., Suwanarusk, R., Russell, B., Renia, L., Nosten, F., Tully, D.C., Kocken, C.H.M., Glynne, R.J., Bodenreider, C., Fidock, D.A., Diagana, T.T. and Winzeler, E.A. (2013). Targeting Plasmodium phosphatidylinositol-4 kinase to eliminate malaria. Nature 504: 248-253. *Co-first
  7. van Schaijk, B.C.L.*, Kumar, T.R.S.*, Vosa, M.W., Richman, A., van Gemerta, G.-J., Li, T., Eappen, A.G., Williamson, K.C., Morahane, B.J., Fishbaugher, M., Kennedy, M., Camargo, N., Khan, S.M., Janse, C.J., Sim, K.L.H., Hoffman, S.L., Kappe, S.H., Sauerwein, R.W., Fidock, D.A.** and Vaughan, A.M.** (2013). Type II fatty acid biosynthesis is essential for Plasmodium falciparum sporozoite development in the midgut of Anopheles mosquitoes. Euk. Cell 13: 550-559. *Co-first, **Co-corresponding
  8. Johnston. G.L., Gething, P.W., Hay, S.I., Smith, D.L. and Fidock, D.A. (2013). Modeling within-host effects of drugs on transmission and prospects for malaria elimination. PLoS Comput. Biol. 9: e1003025.
  9. Wagner, J.C., Goldfless, S.J., Ganesan, S.M., Lee, M.C., Fidock, D.A. and Niles, J.C. (2013). An integrated strategy for efficient vector construction and multi-gene expression in Plasmodium falciparum. Malar. J. 12: 373.
  10. Bobenchik, A.M., Witola, W.H., Augagneur, Y., Lochlainn, L.N., Garg, A., Pachikara, N., Choi, J.-Y., Zhao, Y., Usmani-Brown, S., Lee, A., Adjalley, S.H., Samanta. S., Fidock, D.A., Voelker, D.R., Fikrig, E. and Ben Mamoun, C. (2013). Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission. Proc. Natl. Acad. Sci. USA 110: 18262-18267. PMCID: 3831454.
  11. Fidock, D.A. (2013) Eliminating malaria. Science 340: 1531-1533.
  12. Johnston, G.L., Smith, D.L. and Fidock, D.A. (2013) Malaria's missing number: calculating the human component of R0 by a within-host mechanistic model of Plasmodium falciparum infection and transmission. PLoS Comp. Biol. 9: e1003025.
  13. Falkard, B., Kumar, T.R., Hecht, L.S., Matthews, K.A., Henrich, P.P., Gulati, S., Lewis, R.E., Manary, M.J., Winzeler, E.A., Sinnis, P., Prigge, S.T., Heussler, V., Deschermeier, C. and Fidock, D.A. (2013) A key role for lipoic acid synthesis during Plasmodium liver stage development. Cell Microbiol. 15: 1585-1604.
  14. Ecker, A., Lewis, R.E., Ekland, E.H., Jayabalasingham, B. and Fidock, D.A. (2012) Tricks in Plasmodium's molecular repertoire - Escaping 3'-UTR excision-based conditional silencing of the chloroquine resistance transporter locus. Int. J. Parasitol. 42: 969-974.
  15. Ecker, A., Lehane, A.M., Clain, J. and Fidock, D.A. (2012) PfCRT and its role in antimalarial drug resistance. Trends Parasitol. 28: 504-514.
  16. Lehane, A.M., McDevitt, C.A., Kirk, K. and Fidock, D.A. (2012) Degrees of chloroquine resistance in Plasmodium - is the redox system involved? Int. J. Parasitol. Drugs Drug Resist. 2: 47-57.
  17. Straimer, J., Lee, M.C., Lee, A.H., Zeitler, B., Williams, A.E., Pearl, J.R., Zhang, L., Rebar, E.J., Gregory, P.D., Llinas, M., Urnov, F.D. and Fidock, D.A. (2012) Site-specific genome editing in Plasmodium falciparum using engineered zinc-finger nucleases. Nature Methods 9: 993-998.
  18. Ng, C.L. and Fidock, D.A. (2012) No evidence of decreased artemisinin efficacy in a high-transmission malaria setting in Mali. Am. J. Trop. Med. Hyg. 87: 16-17.
  19. Crabb, B.S., Beeson, J.G., Amino, R., Menard, R., Waters, A., Winzeler, E.A., Wahlgren, M., Fidock, D.A. and Nwaka, S. (2012) Perspectives: The missing pieces. Nature. 484: S22-23.
  20. Uhlemann, A.C. and Fidock, D.A. (2012) Loss of malarial susceptibility to artemisinin in Thailand. Lancet 379: 1928-1930.
  21. Meister, S., Plouffe, D.M., Kuhen, K.L., Bonamy, G.M., Wu, T., Barnes, S.W., Bopp, S.E., Borboa, R., Bright, A.T., Che, J., Cohen, S., Dharia, N.V., Gagaring, K., Gettayacamin, M., Gordon, P., Groessl, T., Kato, N., Lee, M.C., McNamara, C.W., Fidock, D.A., Nagle, A., Nam, T.G., Richmond, W., Roland, J., Rottmann, M., Zhou, B., Froissard, P., Glynne, R.J., Mazier, D., Sattabongkot, J., Schultz, P.G., Tuntland, T., Walker, J.R., Zhou, Y., Chatterjee, A., Diagana, T.T. and Winzeler, E.A. (2011) Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science 334: 1372-1377.
  22. Adjalley, S.H., Johnston, G.L., Li, T., Eastman, R.T., Ekland, E.H., Eappen, A.G., Richman, A., Sim, B.K., Lee, M.C., Hoffman, S.L. and Fidock, D.A. (2011) Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue. Proc. Natl. Acad. Sci. U.S.A. 108: E1214-1223.
  23. Ecker, A., Lakshmanan, V., Sinnis, P., Coppens, I. and Fidock, D.A. (2010). Evidence that mutant PfCRT facilitates the transmission to mosquitoes of chloroquine-treated Plasmodium gametocytes. J. Infect. Dis. 203: 228-236.
  24. Rottmann, M., McNamara, C., Yeung, B.K.S., Lee, M.C.S., Zou, B., Russell, B., Seitz, P., Dharia, N.V., Plouffe, D.M., Tan, J., Cohen, S.B., Spencer, K.R., Gonzalez-Paez, G.E., Lakshminarayana, S.B., Goh, A., Suwanarusk, R., Jegla, T., Schmitt, E.K., Beck, H.-P., Brun, R., Nosten, F., Renia, L., Dartois, V., Keller, T.H., Fidock, D.A., Winzeler, E.A. and Diagana, T.T. (2010). Spiroindolones, a new and potent chemotype for the treatment of malaria. Science 329: 1175-1180.
  25. Valderramos S.G., Scanfeld D., Uhlemann A.-C., Fidock D.A.* and Krishna S.* (2010). Investigations into the role of the Plasmodium falciparum SERCA (PfATP6) L263E mutation in artemisinin action and resistance. Antimicrob Agents Chemother. 54: 3842-3852. *Co-equal and co-corresponding
  26. Valderramos, S.G., Valderramos J.C., Musset L., Purcell L.A., Mercereau-Puijalon O., Legrand E. and Fidock D.A. (2010). Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum. PLoS Pathogens 6: e1000887. pdf
  27. Fidock, D.A. (2010). Drug discovery: Priming the antimalarial pipeline. Nature 465: 297-8.
  28. Melcher M., Muhle R.A., Henrich P., Kraemer S.M., Avril M., Vigan-Womas I., Mercereau-Puijalon O., Smith J.D. and Fidock D.A. (2010) Identification of a role for the PfEMP1 semi-conserved head structure in protein trafficking to the surface of Plasmodium falciparum infected red blood cells. Cell Microbiol. (in press). pdf
  29. Eastman, R.E. and Fidock, D.A. (2009). Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nature Rev. Microbiol. 7: 864-874. pdf
  30. Yuan, J., Johnson, R.L., Huang, R., Wichterman, J., Jiang, H., Hayton, K., Fidock, D.A., Wellems, T.E., Inglese, J., Austin, C.P. and Su, X-z. (2009). Screening and genetic mapping targets of differential chemical-response phenotypes in Plasmodium falciparum. Nature Chem. Biol. 5: 765-771. pdf
  31. Dharia, N.V., Sidhu, A.B.S., Cassera, M.C., Westenberger, S., Bopp, S., Eastman, R.T., Plouffe, D., Batalov, S., Park, D.J., Volkman, S.K., Wirth, D.W., Zhou, Y., Fidock, D.A. and Winzeler, E.A. (2009). Use of high-density tiling microarrays to globally identify mutations and elucidate mechanisms of drug resistance in Plasmodium falciparum. Genome Biol. 10: R21. pdf
  32. Yu, M., Kumar, T.R.S., Nkrumah, L.J., Coppi, A., Retzlaff, S., Li, C.D., Kelly, B.J., Moura, P.A., Lakshmanan, V., Freundlich, J.S., Valderramos, J.C., Vilcheze, C., Siedner, M., Tsai, J.H.C., Falkard, B., Sidhu, A.B.S., Purcell, L.A., Gratraud, P., Kremer, L., Waters, A.P., Schiehser, G., Jacobus, D.P., Janse, C.J., Ager, A., Jacobs, Jr. W.R., Sacchettini, J.C., Heussler, V., Sinnis, P. and Fidock, D.A. (2008). The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites. Cell Host & Microbe.11: 567-578. Cover article featured in the same issue of Cell Host & Microbe and reviewed in Nature Reviews in Microbiology 7: 94. pdf
  33. Fidock, D.A., Eastman, R.E., Ward, S.A. and Meshnick, S.R. (2008). Recent highlights in antimalarial drug resistance and chemotherapy research. Trends in Parasitol. 24: 537-544. pdf
  34. Lee, M.C.S., Moura, P.A., Miller, E.A. and Fidock, D.A. (2008). Plasmodium falciparum Sec24 marks transitional ER that exports a model cargo via a diacidic motif. Mol. Microbiol. 68: 1535-1546. pdf
  35. Ekland, E.H. and Fidock, D.A. (2008). In vitro evaluations of antimalarial drugs and their relevance to clinical outcomes. Int. J. Parasitol. 38: 743-747. pdf
  36. Greenwood, B.M., Fidock, D.A., Kyle, D.E., Kappe, S.H., Collins, F.H. and Duffy, P.E. (2008). Malaria: progress, perils, and prospects for eradication. J. Clin. Invest. 118: 1266-1276. pdf
  37. Lee, M.C.S. and Fidock, D.A. (2008). Arresting malaria parasite egress from infected red blood cells. Nature Chem. Biol. 4: 161-162. pdf
  38. Ekland, E.H. and Fidock, D.A. (2007). Advances in understanding the genetic basis of antimalarial drug resistance. Curr. Opinion Microbiol. 10: 363-370.
  39. Hunt, P., Afonso, A., Creasey, A., Culleton, R., Sidhu, A.B.S., Logan, J., Valderramos, S., McNae, I., Cheesman, S., do Rosario, V., Carter, R., Fidock, D.A. and Cravo, P. (2007). Gene encoding a de-ubiquitinating enzyme is mutated in artemisinin- and chloroquine-resistant rodent malaria parasites. Mol. Microbiol. 65: 27-40.
  40. Sidhu, A.B., Sun, Q., Nkrumah, L.J., Dunne, M.W., Sacchettini, J.C. and Fidock, D.A. (2007). In vitro efficacy, resistance selection, and structural modeling studies implicate the malarial parasite apicoplast as the target of azithromycin. J. Biol. Chem. 282: 2494-2504.
  41. Nkrumah L.N., Muhle R.A., Moura P.A., Ghosh P., Hatfull G., Jacobs Jr. W.R. and Fidock D.A. (2006). Efficient site-specific integration in Plasmodium falciparum chromosomes mediated by mycobacteriophage Bxb1 integrase. Nature Methods 3: 615-621. pdf
  42. Lakshmanan, V., Bray, P.G., Verdier-Pinard, D., Johnson, D.J., Horrocks, P., Muhle, R.A., Alakpa, G.E., Hughes, R.H., Ward, S.A., Krogstad, D.J., Sidhu, A.B.S. and Fidock, D.A. (2005). A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance. EMBO J. 24: 2294-2305. pdf
  43. Johnson, D.J., Fidock, D.A.*, Mungthin, M., Lakshmanan, V., Sidhu, A.B.S., Bray, P.G., and Ward, S.A.* (2004) Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Mol. Cell 15: 867-877. (*Co-corresponding authors) pdf
  44. Fidock, D.A., Rosenthal, P.J., Croft, S.L., Brun, R. and Nwaka, S. (2004). Antimalarial drug discovery: efficacy models for compound screening. Nature Rev. Drug Disc. 3: 509-520. pdf
  45. Sidhu, A.B.S., Verdier-Pinard, D. and Fidock, D.A. (2002). pfcrt mutations confer chloroquine resistance to Plasmodium falciparum malaria parasites. Science 298: 210-213. pdf
  46. Djimde, A., Doumbo, O.K., Cortese, J.F., Kayentao, K., Doumbo, S., Diourte, Y., Coulibaly, D., Dicko, A., Su, X-z., Nomura, T., Fidock, D.A., Wellems, T.E. and Plowe, C.V. (2001). A molecular marker for chloroquine resistant falciparum malaria. New Engl. J. Med. 344: 257-63.
  47. Fidock, D.A., Nomura, T., Talley, A.K., Cooper, R.A., Dzekunov, S.M., Ferdig, M.T., Ursos, L.M., Sidhu, A.B.S., Deitsch, K., Su, X-z., Wootton, J.C., Roepe, P.D. and Wellems, T.E. (2000). Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6: 681-71. pdf

Professor David A. Fidock
Phone: 212-305-0816
Lab Phone: 212-305-6958
Fax: 212-305-4038
Email: df2260@columbia.edu
Website: microbiology.columbia.edu/fidock


Department of Microbiology & Immunology, Columbia University + 701 W. 168 St., HHSC 1208 New York, NY 10032 Tel. 212-305-3647