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The evolutionary landscape of antifolate resistance in Plasmodium falciparum

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Abstract

Resistance to antifolates in Plasmodium falciparum is well described and has been observed in clinical settings for decades. At the molecular level, point mutations in the dhfr gene that lead to resistance have been identified, and the crystal structure of the wildtype and mutant dihydrofolate reductase enzymes have been solved in complex with native substrate and drugs. However, we are only beginning to understand the complexities of the evolutionary pressures that lead to the evolution of drug resistance in this system. Microbial systems that allow heterologous expression of malarial proteins provide a tractable way to investigate patterns of evolution that can inform our eventual understanding of the more complex factors that influence the evolution of drug resistance in clinical settings. In this paper we will review work in Escherichia coli and Saccharomyces cerevisiae expression systems that explore the fitness landscape of mutations implicated in drug resistance and show that (i) a limited number of evolutionary pathways to resistance are followed with high probability; (ii) fitness costs associated with the maintenance of high levels of resistance are modes; and (iii) different antifolates may exert opposing selective forces.

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References

  • Abdel-Muhsin A. A., Mackinnon M. J., Ali E., Nassir E. A., Suleiman S., Ahmed S. et al. 2004 Evolution of drug-resistance genes in Plasmodium falciparum in an area of seasonal malaria transmission in eastern Sudan. J. Infect. Dis. 189, 1239–1244.

    Article  PubMed  CAS  Google Scholar 

  • Agur Z. and Slobodkin L. 1986 Environmental fluctuations - how do they affect the topography of the adaptive landscape. J. Genet. 65, 45–54.

    Article  Google Scholar 

  • Andersson D. I. 2006 The biological cost of mutational antibiotic resistance: any practical conclusions? Curr. Opin. Microbiol. 9, 461–465.

    Article  PubMed  CAS  Google Scholar 

  • Brown K. M., Costanzo M. S., Xu W., Roy S., Lozovsky E. R. and Hartl D. L. 2010 Compensatory mutations restore fitness during the evolution of dihydrofolate reductase. Mol. Biol. Evol. 27, 2682–2690.

    Article  PubMed  CAS  Google Scholar 

  • Chusacultanachai S., Thiensathit P., Tarnchompoo B., Sirawaraporn W. and Yuthavong Y. 2002 Novel antifolate resistant mutations of Plasmodium falciparum dihydrofolate reductase selected in Escherichia coli. Mol. Biochem. Parasitol. 120, 61–72.

    Article  PubMed  CAS  Google Scholar 

  • Costanzo M. S., Brown K. M. and D. L Hartl 2011 Fitness trade-offs in the evolution of drug resistance in dihydrofolate reductase in Plasmodium falcipaurm. PLoS ONE 6, e19636.

    Article  PubMed  CAS  Google Scholar 

  • Cowman A. F., Morry M. J., Biggs B. A., Cross G. A. and Foote S. J. 1988 Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 85, 9109–9113.

    Article  PubMed  CAS  Google Scholar 

  • Diggens S. M., Gutteridge W. E. and Trigg P. I. 1970 Altered dihydrofolate reductase associated with a pyrimethamine-resistant Plasmodium berghei berghei produced in a single step. Nature 228, 579–580.

    Article  PubMed  CAS  Google Scholar 

  • Gregson A. and Plowe C. V. 2005 Mechanisms of resistance of malaria parasites to antifolates. Pharmacol. Rev. 57, 117–145.

    Article  PubMed  CAS  Google Scholar 

  • Kublin J. G., Fraction K. Dzinjalamala, Kamwendo D. D., Malkin E. M., Cortese J. F. et al. 2002 Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J. Infect. Dis. 185, 380–388.

    Article  PubMed  CAS  Google Scholar 

  • Lozovsky E. R., Chookajorn T., Brown K. M., Imwong M., Shaw P. J., Kamchonwongpaisan S. et al. 2009 Stepwise acquisition of pyrimethamine resistance in the malaria parasite. Proc. Natl. Acad. Sci. USA 106, 12025–12030.

    Article  PubMed  CAS  Google Scholar 

  • Mita T., Tanabe K., Takahashi N., Culleton R., Ndounga M., Dzodzomenyo M. et al. 2008 Indigenous evolution of Plasmodium falciparum pyrimethamine resistance multiple times in Africa. J. Antimicrob. Chemother. 68, 413–415.

    Google Scholar 

  • Nzila-Mounda A., Mberu E. K., Sibley C. H., Plowe C. V., Winstanley P. A. and Watkins W. M. 1998 Kenyan Plasmodium falciparum field isolates: correlation between pyrimethamine and chlorcycloguanil activity in vitro and point mutations in the dihydrofolate reductase domain. Antimicrob. Agents Chemother. 42, 164–169.

    PubMed  CAS  Google Scholar 

  • Nzila-Mounda A., Mberu E. K., Sibley C. H., Plowe C. V., Winstanley P. A. and Watkins W. M. 1998b Kenyan Plasmodium falciparum field isolates: correlation between pyrimethamine and chlorcycloguanil activity in vitro and point mutations in the dihydrofolate reductase domain. Antimicrob. Agents Chemother. 42, 164–169.

    PubMed  CAS  Google Scholar 

  • Peterson D. S., Walliker D. and Wellems T. E. 1988 Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proc. Natl. Acad. Sci. USA 85, 9114–9118.

    Article  PubMed  CAS  Google Scholar 

  • Rastelli G., Sirawaraporn W., Sompornpisut P., Vilaivan T., Kamchonwongpaisan S., Quarrell R. et al. 2000 Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: structural basis of antifolate resistance. Bioorg. Med. Chem. 8, 1117–1128.

    Article  PubMed  CAS  Google Scholar 

  • Salverda M. L. M., de Visser J. A. G. M. and Barlow M. 2010 Natural evolution of TEM-1 β-lactamase: experimental reconstruction and clinical relevance. FEMS Microbiol. Rev. 34, 1015–1036.

    PubMed  CAS  Google Scholar 

  • Salverda M. L. M., Merijn L. M., Salverda E., Dellus F. A., Gorter A. J. M., Debets J. et al. 2011 Initial mutations direct alternative pathways of protein evolution. PLoS Genet. 7, e1001321.

    Article  Google Scholar 

  • Sandefur C. I., Wooden J. M., Quaye I. K., Sirawaraporn W. and Sibley C. H. 2007 Pyrimethamine-resistant dihydrofolate reductase enzymes of Plasmodium falciparum are not enzymatically compromised in vitro. Mol. Biochem. Parasitol. 154, 1–5.

    Article  PubMed  CAS  Google Scholar 

  • Sibley C. H., Hyde J. E., Sims P. F. G., Plowe C. V., Kublin J. G., Mberu E. K. et al. 2001 Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? Trends Parasitol. 17, 582–588.

    Article  PubMed  CAS  Google Scholar 

  • Sirawaraporn W., Sathitkul T., Sirawaraporn R., Yuthavong Y. and Santi D. 1997 Antifolate-resistant mutants of Plasmodium falciparum dihydrofolatereductase. Proc. Natl. Acad. Sci. USA 94, 1124–1129.

    Article  PubMed  CAS  Google Scholar 

  • Sirawaraporn W., Sirawaraporn R., Cowman A. F., Yuthavong Y. and Santi D. V. 1990 Heterologous expression of active thymidylate synthase-dihydrofolate reductase from Plasmodium falciparum. Biochemistry 29, 10779–10785.

    Article  PubMed  CAS  Google Scholar 

  • Thompson P. E. and Bayles A. 1968 Reciprocal cross resistance between cycloguanil hydrochloride and pyrimethamine in Plasmodium berghei infections in mice. J. Parasitol. 54, 588–593.

    Article  PubMed  CAS  Google Scholar 

  • Walliker D., Hunt P. and Babiker H. 2005 Fitness of drug-resistant malaria parasites. Acta Tropica 94, 251–259.

    Article  PubMed  CAS  Google Scholar 

  • Wang P., Lee C., Bayoumi R., Djimde A., Doumbo O., Swedberg G. et al. 1997 Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. Mol. Biochem. Parasitol. 89, 161–177.

    Article  PubMed  CAS  Google Scholar 

  • Weinreich D. M., Delaney N. F., DePristo M. A. and Hartl D. L. 2006 Darwinian evolution can follow only very few mutational paths to fitter proteins. Science 312, 111–114.

    Article  PubMed  CAS  Google Scholar 

  • Wooden J. M., Hartwell L. H., Vasquez B. and Hopkins Sibley C. 1997 Analysis in yeast of antimalaria drugs that target the dihydrofolate reductase of Plasmodium falciparum. Mol. Biochem. Parasitol. 85, 25–40.

    Article  PubMed  CAS  Google Scholar 

  • Zhou Z., Griffing S. M., de Oliveira A. M., McCollum A. M., Quezada W. M., Arrospide N. et al. 2008 Decline in sulfadoxine-pyrimethamine-resistant alleles after change in drug policy in the amazon region of Peru. Antimicrob. Agents Chemother. 52, 739–741.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, 02138, USA

    MARNA S. COSTANZO & DANIEL L. HARTL

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  1. MARNA S. COSTANZO
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  2. DANIEL L. HARTL
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Correspondence to DANIEL L. HARTL.

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[Costanzo M. S. and Hartl D. L. 2011 The evolutionary landscape of antifolate resistance in Plasmodium falciparum. J. Genet. 90, 187-190]

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COSTANZO, M.S., HARTL, D.L. The evolutionary landscape of antifolate resistance in Plasmodium falciparum . J Genet 90, 187–190 (2011). https://doi.org/10.1007/s12041-011-0072-z

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  • DOI: https://doi.org/10.1007/s12041-011-0072-z

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