1932

Abstract

Understanding and controlling the spread of antimalarial resistance, particularly to artemisinin and its partner drugs, is a top priority. parasites resistant to chloroquine, amodiaquine, or piperaquine harbor mutations in the chloroquine resistance transporter (PfCRT), a transporter resident on the digestive vacuole membrane that in its variant forms can transport these weak-base 4-aminoquinoline drugs out of this acidic organelle, thus preventing these drugs from binding heme and inhibiting its detoxification. The structure of PfCRT, solved by cryogenic electron microscopy, shows mutations surrounding an electronegative central drug-binding cavity where they presumably interact with drugs and natural substrates to control transport. susceptibility to heme-binding antimalarials is also modulated by overexpression or mutations in the digestive vacuole membrane–bound ABC transporter PfMDR1 ( multidrug resistance 1 transporter). Artemisinin resistance is primarily mediated by mutations in Kelch13 protein (K13), a protein involved in multiple intracellular processes including endocytosis of hemoglobin, which is required for parasite growth and artemisinin activation. Combating drug-resistant malaria urgently requires the development of new antimalarial drugs with novel modes of action.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-micro-020518-115546
2020-09-08
2024-10-07
Loading full text...

Full text loading...

/deliver/fulltext/micro/74/1/annurev-micro-020518-115546.html?itemId=/content/journals/10.1146/annurev-micro-020518-115546&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Agrawal S, Moser KA, Morton L, Cummings MP, Parihar A et al. 2017. Association of a novel mutation in the Plasmodium falciparum chloroquine resistance transporter with decreased piperaquine sensitivity. J. Infect. Dis. 216:468–76
    [Google Scholar]
  2. 2. 
    Amaratunga C, Lim P, Suon S, Sreng S, Mao S et al. 2016. Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect. Dis. 16:357–65
    [Google Scholar]
  3. 3. 
    Amato R, Lim P, Miotto O, Amaratunga C, Dek D et al. 2017. Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study. Lancet Infect. Dis. 17:164–73
    [Google Scholar]
  4. 4. 
    Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC et al. 2014. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505:50–55
    [Google Scholar]
  5. 5. 
    Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P et al. 2014. Spread of artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 371:411–23
    [Google Scholar]
  6. 6. 
    Babbitt SE, Altenhofen L, Cobbold SA, Istvan ES, Fennell C et al. 2012. Plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state. PNAS 109:E3278–87
    [Google Scholar]
  7. 7. 
    Bakouh N, Bellanca S, Nyboer B, Moliner Cubel S, Karim Z et al. 2017. Iron is a substrate of the Plasmodium falciparum chloroquine resistance transporter PfCRT in Xenopus oocytes. J. Biol. Chem. 292:16109–21
    [Google Scholar]
  8. 8. 
    Baro NK, Pooput C, Roepe PD 2011. Analysis of chloroquine resistance transporter (CRT) isoforms and orthologues in S. cerevisiae yeast. Biochemistry 50:6701–10
    [Google Scholar]
  9. 9. 
    Barrett MP, Kyle DE, Sibley LD, Radke JB, Tarleton RL 2019. Protozoan persister-like cells and drug treatment failure. Nat. Rev. Microbiol. 17:607–20
    [Google Scholar]
  10. 10. 
    Bellanca S, Summers RL, Meyrath M, Dave A, Nash MN et al. 2014. Multiple drugs compete for transport via the Plasmodium falciparum chloroquine resistance transporter at distinct but interdependent sites. J. Biol. Chem. 289:36336–51
    [Google Scholar]
  11. 11. 
    Bhattacharjee S, Coppens I, Mbengue A, Suresh N, Ghorbal M et al. 2018. Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance. Blood 131:1234–47
    [Google Scholar]
  12. 12. 
    Birnbaum J, Flemming S, Reichard N, Soares AB, Mesen-Ramirez P et al. 2017. A genetic system to study Plasmodium falciparum protein function. Nat. Methods 14:450–56
    [Google Scholar]
  13. 13. 
    Birnbaum J, Scharf S, Schmidt S, Jonscher E, Hoeijmakers WAM et al. 2020. A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites. Science 367:51–59
    [Google Scholar]
  14. 14. 
    Blasco B, Leroy D, Fidock DA 2017. Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic. Nat. Med. 23:917–28
    [Google Scholar]
  15. 15. 
    Bopp S, Magistrado P, Wong W, Schaffner SF, Mukherjee A et al. 2018. Plasmepsin II-III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum. Nat. Commun 9:1769
    [Google Scholar]
  16. 16. 
    Bray PG, Mungthin M, Hastings IM, Biagini GA, Saidu DK et al. 2006. PfCRT and the trans-vacuolar proton electrochemical gradient: regulating the access of chloroquine to ferriprotoporphyrin IX. Mol. Microbiol. 62:238–51
    [Google Scholar]
  17. 17. 
    Bridgford JL, Xie SC, Cobbold SA, Pasaje CFA, Herrmann S et al. 2018. Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome. Nat. Commun. 9:3801
    [Google Scholar]
  18. 18. 
    Bunditvorapoom D, Kochakarn T, Kotanan N, Modchang C, Kumpornsin K et al. 2018. Fitness loss under amino acid starvation in artemisinin-resistant Plasmodium falciparum isolates from Cambodia. Sci. Rep. 8:12622
    [Google Scholar]
  19. 19. 
    Callaghan PS, Hassett MR, Roepe PD 2015. Functional comparison of 45 naturally occurring isoforms of the Plasmodium falciparum chloroquine resistance transporter (PfCRT). Biochemistry 54:5083–94
    [Google Scholar]
  20. 20. 
    Cerqueira GC, Cheeseman IH, Schaffner SF, Nair S, McDew-White M et al. 2017. Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance. Genome Biol 18:78
    [Google Scholar]
  21. 21. 
    Chaorattanakawee S, Saunders DL, Sea D, Chanarat N, Yingyuen K et al. 2015. Ex vivo drug susceptibility testing and molecular profiling of clinical Plasmodium falciparum isolates from Cambodia from 2008 to 2013 suggest emerging piperaquine resistance. Antimicrob. Agents Chemother. 59:4631–43
    [Google Scholar]
  22. 22. 
    Cheeseman IH, Miller BA, Nair S, Nkhoma S, Tan A et al. 2012. A major genome region underlying artemisinin resistance in malaria. Science 336:79–82
    [Google Scholar]
  23. 23. 
    Chen N, LaCrue AN, Teuscher F, Waters NC, Gatton ML et al. 2014. Fatty acid synthesis and pyruvate metabolism pathways remain active in dihydroartemisinin-induced dormant ring stages of Plasmodium falciparum.Antimicrob. Agents Chemother 58:4773–81
    [Google Scholar]
  24. 24. 
    Chenet SM, Akinyi Okoth S, Huber CS, Chandrabose J, Lucchi NW et al. 2016. Independent emergence of the Plasmodium falciparum Kelch propeller domain mutant allele C580Y in Guyana. J. Infect. Dis. 213:1472–75
    [Google Scholar]
  25. 25. 
    Cheng Q, Kyle DE, Gatton ML 2012. Artemisinin resistance in Plasmodium falciparum: a process linked to dormancy. Int. J. Parasitol. Drugs Drug Resist. 2:249–55
    [Google Scholar]
  26. 26. 
    Combrinck JM, Fong KY, Gibhard L, Smith PJ, Wright DW, Egan TJ 2015. Optimization of a multi-well colorimetric assay to determine haem species in Plasmodium falciparum in the presence of anti-malarials. Malar. J. 14:253
    [Google Scholar]
  27. 27. 
    Combrinck JM, Mabotha TE, Ncokazi KK, Ambele MA, Taylor D et al. 2013. Insights into the role of heme in the mechanism of action of antimalarials. ACS Chem. Biol. 8:133–37
    [Google Scholar]
  28. 28. 
    Conrad MD, Rosenthal PJ. 2019. Antimalarial drug resistance in Africa: the calm before the storm. Lancet Infect. Dis. 19:e338–51
    [Google Scholar]
  29. 29. 
    Cooper RA, Ferdig MT, Su XZ, Ursos LM, Mu J et al. 2002. Alternative mutations at position 76 of the vacuolar transmembrane protein PfCRT are associated with chloroquine resistance and unique stereospecific quinine and quinidine responses in Plasmodium falciparum. Mol. Pharmacol 61:35–42
    [Google Scholar]
  30. 30. 
    Cowell A, Winzeler E. 2018. Exploration of the Plasmodium falciparum resistome and druggable genome reveals new mechanisms of drug resistance and antimalarial targets. Microbiol. Insights 11:1178636118808529
    [Google Scholar]
  31. 31. 
    Demas AR, Sharma AI, Wong W, Early AM, Redmond S et al. 2018. Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility. PNAS 115:12799–804
    [Google Scholar]
  32. 32. 
    Dhingra SK, Redhi D, Combrinck JM, Yeo T, Okombo J et al. 2017. A variant PfCRT isoform can contribute to Plasmodium falciparum resistance to the first-line partner drug piperaquine. mBio 8:e00303–17
    [Google Scholar]
  33. 33. 
    Dhingra SK, Small-Saunders JL, Menard D, Fidock DA 2019. Plasmodium falciparum resistance to piperaquine driven by PfCRT. Lancet Infect. Dis. 19:1168–69
    [Google Scholar]
  34. 34. 
    Dini S, Zaloumis S, Cao P, Price RN, Fowkes FJI et al. 2018. Investigating the efficacy of triple artemisinin-based combination therapies for treating Plasmodium falciparum malaria patients using mathematical modeling. Antimicrob. Agents Chemother. 62:e01068–18
    [Google Scholar]
  35. 35. 
    Dogovski C, Xie SC, Burgio G, Bridgford J, Mok S et al. 2015. Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance. PLOS Biol 13:e1002132
    [Google Scholar]
  36. 36. 
    Dondorp AM, Nosten F, Yi P, Das D, Phyo AP et al. 2009. Artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 361:455–67
    [Google Scholar]
  37. 37. 
    Dorn A, Vippagunta SR, Matile H, Jaquet C, Vennerstrom JL, Ridley RG 1998. An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerisation by quinoline antimalarials. Biochem. Pharmacol. 55:727–36
    [Google Scholar]
  38. 38. 
    Duru V, Khim N, Leang R, Kim S, Domergue A et al. 2015. Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations. BMC Med 13:305
    [Google Scholar]
  39. 39. 
    Dworkin J, Shah IM. 2010. Exit from dormancy in microbial organisms. Nat. Rev. Microbiol. 8:890–96
    [Google Scholar]
  40. 40. 
    Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM et al. 2000. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6:861–71
    [Google Scholar]
  41. 41. 
    Frosch AE, Laufer MK, Mathanga DP, Takala-Harrison S, Skarbinski J et al. 2014. Return of widespread chloroquine-sensitive Plasmodium falciparum to Malawi. J. Infect. Dis. 210:1110–14
    [Google Scholar]
  42. 42. 
    Gabryszewski SJ, Modchang C, Musset L, Chookajorn T, Fidock DA 2016. Combinatorial genetic modeling of pfcrt-mediated drug resistance evolution in Plasmodium falciparum. Mol. Biol. Evol 33:1554–70
    [Google Scholar]
  43. 43. 
    Gething PW, Casey DC, Weiss DJ, Bisanzio D, Bhatt S et al. 2016. Mapping Plasmodium falciparum mortality in Africa between 1990 and 2015. N. Engl. J. Med. 375:2435–45
    [Google Scholar]
  44. 44. 
    Ghorbal M, Gorman M, Macpherson CR, Martins RM, Scherf A, Lopez-Rubio JJ 2014. Genome editing in the human malaria parasite Plasmodium falciparum using the CRISPR-Cas9 system. Nat. Biotechnol. 32:819–21
    [Google Scholar]
  45. 45. 
    Gibbons J, Button-Simons KA, Adapa SR, Li S, Pietsch M et al. 2018. Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum. BMC Genom 19:849
    [Google Scholar]
  46. 46. 
    Gnädig NF, Stokes BH, Edwards RL, Kalantarov GF, Heimsch KC et al. 2020. Insights into the intracellular localization, protein associations and artemisinin resistance properties of Plasmodium falciparum K13. PLOS Pathog 16:e1008482
    [Google Scholar]
  47. 47. 
    Goldberg DE. 2013. Complex nature of malaria parasite hemoglobin degradation. PNAS 110:5283–84. Erratum. 2013 PNAS 110:177097
    [Google Scholar]
  48. 48. 
    Goodman CD, Siregar JE, Mollard V, Vega-Rodriguez J, Syafruddin D et al. 2016. Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes. Science 352:349–53
    [Google Scholar]
  49. 49. 
    Gorka AP, de Dios A, Roepe PD 2013. Quinoline drug-heme interactions and implications for antimalarial cytostatic versus cytocidal activities. J. Med. Chem. 56:5231–46
    [Google Scholar]
  50. 50. 
    Gray KA, Gresty KJ, Chen N, Zhang V, Gutteridge CE et al. 2016. Correlation between cyclin dependent kinases and artemisinin-induced dormancy in Plasmodium falciparum in vitro. PLOS ONE 11:e0157906
    [Google Scholar]
  51. 51. 
    Hamilton WL, Amato R, van der Pluijm RW, Jacob CG, Quang HH et al. 2019. Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study. Lancet Infect. Dis. 19:943–51
    [Google Scholar]
  52. 52. 
    Hayward R, Saliba KJ, Kirk K 2005. pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum. Mol. Microbiol 55:1285–95
    [Google Scholar]
  53. 53. 
    Heinberg A, Kirkman L. 2015. The molecular basis of antifolate resistance in Plasmodium falciparum: looking beyond point mutations. Ann. N. Y. Acad. Sci. 1342:10–18
    [Google Scholar]
  54. 54. 
    Heller LE, Goggins E, Roepe PD 2018. Dihydroartemisinin-ferriprotoporphyrin IX adduct abundance in Plasmodium falciparum malarial parasites and the relationship to emerging artemisinin resistance. Biochemistry 57:6935–45
    [Google Scholar]
  55. 55. 
    Heller LE, Roepe PD. 2018. Quantification of free ferriprotoporphyrin IX heme and hemozoin for artemisinin sensitive versus delayed clearance phenotype Plasmodium falciparum malarial parasites. Biochemistry 57:6927–34
    [Google Scholar]
  56. 56. 
    Henrici RC, van Schalkwyk DA, Sutherland CJ 2019. Modification of pfap2mu and pfubp1 markedly reduces ring-stage susceptibility of Plasmodium falciparum to artemisinin in vitro.Antimicrob. Agents Chemother 64:e01542–19
    [Google Scholar]
  57. 57. 
    Henrici RC, van Schalkwyk DA, Sutherland CJ 2019. Transient temperature fluctuations severely decrease P. falciparum susceptibility to artemisinin in vitro. Int. J. Parasitol. Drugs Drug Resist 9:23–26
    [Google Scholar]
  58. 58. 
    Hott A, Casandra D, Sparks KN, Morton LC, Castanares GG et al. 2015. Artemisinin-resistant Plasmodium falciparum parasites exhibit altered patterns of development in infected erythrocytes. Antimicrob. Agents Chemother. 59:3156–67
    [Google Scholar]
  59. 59. 
    Huang F, Takala-Harrison S, Jacob CG, Liu H, Sun X et al. 2015. A single mutation in K13 predominates in Southern China and is associated with delayed clearance of Plasmodium falciparum following artemisinin treatment. J. Infect. Dis. 212:1629–35
    [Google Scholar]
  60. 60. 
    Hunt P, Afonso A, Creasey A, Culleton R, Sidhu AB et al. 2007. Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites. Mol. Microbiol. 65:27–40
    [Google Scholar]
  61. 61. 
    Imwong M, Dondorp AM, Nosten F, Yi P, Mungthin M et al. 2010. Exploring the contribution of candidate genes to artemisinin resistance in Plasmodium falciparum.Antimicrob. Agents Chemother 54:2886–92
    [Google Scholar]
  62. 62. 
    Imwong M, Hien TT, Thuy-Nhien NT, Dondorp AM, White NJ 2017. Spread of a single multidrug resistant malaria parasite lineage (PfPailin) to Vietnam. Lancet Infect. Dis. 17:1022–23
    [Google Scholar]
  63. 63. 
    Imwong M, Suwannasin K, Kunasol C, Sutawong K, Mayxay M et al. 2017. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study. Lancet Infect. Dis. 17:491–97
    [Google Scholar]
  64. 64. 
    Ismail HM, Barton V, Phanchana M, Charoensutthivarakul S, Wong MH et al. 2016. Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7. PNAS 113:2080–85
    [Google Scholar]
  65. 65. 
    Jones SE, Lennon JT. 2010. Dormancy contributes to the maintenance of microbial diversity. PNAS 107:5881–86
    [Google Scholar]
  66. 66. 
    Juge N, Moriyama S, Miyaji T, Kawakami M, Iwai H et al. 2015. Plasmodium falciparum chloroquine resistance transporter is a H+-coupled polyspecific nutrient and drug exporter. PNAS 112:3356–61
    [Google Scholar]
  67. 67. 
    Kim J, Tan YZ, Wicht KJ, Erramilli SK, Dhingra SK et al. 2019. Structure and drug resistance of the Plasmodium falciparum transporter PfCRT. Nature 576:315–20
    [Google Scholar]
  68. 68. 
    Klonis N, Crespo-Ortiz MP, Bottova I, Abu-Bakar N, Kenny S et al. 2011. Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion. PNAS 108:11405–10
    [Google Scholar]
  69. 69. 
    Klonis N, Xie SC, McCaw JM, Crespo-Ortiz MP, Zaloumis SG et al. 2013. Altered temporal response of malaria parasites determines differential sensitivity to artemisinin. PNAS 110:5157–62
    [Google Scholar]
  70. 70. 
    Kuhn Y, Rohrbach P, Lanzer M 2007. Quantitative pH measurements in Plasmodium falciparum-infected erythrocytes using pHluorin. Cell Microbiol 9:1004–13
    [Google Scholar]
  71. 71. 
    LaCrue AN, Scheel M, Kennedy K, Kumar N, Kyle DE 2011. Effects of artesunate on parasite recrudescence and dormancy in the rodent malaria model Plasmodium vinckei. PLOS ONE 6:e26689
    [Google Scholar]
  72. 72. 
    Lee AH, Dhingra SK, Lewis IA, Singh MK, Siriwardana A et al. 2018. Evidence for regulation of hemoglobin metabolism and intracellular ionic flux by the Plasmodium falciparum chloroquine resistance transporter. Sci. Rep. 8:13578
    [Google Scholar]
  73. 73. 
    Lehane AM, Hayward R, Saliba KJ, Kirk K 2008. A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites. J. Cell Sci. 121:1624–32
    [Google Scholar]
  74. 74. 
    Lehane AM, van Schalkwyk DA, Valderramos SG, Fidock DA, Kirk K 2011. Differential drug efflux or accumulation does not explain variation in the chloroquine response of Plasmodium falciparum strains expressing the same isoform of mutant PfCRT. Antimicrob. Agents Chemother. 55:2310–18
    [Google Scholar]
  75. 75. 
    Lewis IA, Wacker M, Olszewski KL, Cobbold SA, Baska KS et al. 2014. Metabolic QTL analysis links chloroquine resistance in Plasmodium falciparum to impaired hemoglobin catabolism. PLOS Genet 10:e1004085
    [Google Scholar]
  76. 76. 
    Li H, O'Donoghue AJ, van der Linden WA, Xie SC, Yoo E et al. 2016. Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature 530:233–36
    [Google Scholar]
  77. 77. 
    Li W, Mo W, Shen D, Sun L, Wang J et al. 2005. Yeast model uncovers dual roles of mitochondria in action of artemisinin. PLOS Genet 1:e36
    [Google Scholar]
  78. 78. 
    Loesbanluechai D, Kotanan N, de Cozar C, Kochakarn T, Ansbro MR et al. 2019. Overexpression of plasmepsin II and plasmepsin III does not directly cause reduction in Plasmodium falciparum sensitivity to artesunate, chloroquine and piperaquine. Int. J. Parasitol. Drugs Drug Resist. 9:16–22
    [Google Scholar]
  79. 79. 
    Lu F, Culleton R, Zhang M, Ramaprasad A, von Seidlein L et al. 2017. Emergence of indigenous artemisinin-resistant Plasmodium falciparum in Africa. N. Engl. J. Med. 376:991–93
    [Google Scholar]
  80. 80. 
    MalariaGen Plasmodium falciparum Community Proj 2016. Genomic epidemiology of artemisinin resistant malaria. eLife 5:e08714
    [Google Scholar]
  81. 81. 
    Martin RE, Marchetti RV, Cowan AI, Howitt SM, Broer S, Kirk K 2009. Chloroquine transport via the malaria parasite's chloroquine resistance transporter. Science 325:1680–82
    [Google Scholar]
  82. 82. 
    Mathieu LC, Cox H, Early AM, Mok S, Lazrek Y et al. 2020. Local emergence in Amazonia of Plasmodium falciparum k13 C580Y mutants associated with in vitro artemisinin resistance. eLife 9:e51015
    [Google Scholar]
  83. 83. 
    Maude RJ, Nguon C, Dondorp AM, White LJ, White NJ 2014. The diminishing returns of atovaquone-proguanil for elimination of Plasmodium falciparum malaria: modelling mass drug administration and treatment. Malar. J. 13:380
    [Google Scholar]
  84. 84. 
    Mbengue A, Bhattacharjee S, Pandharkar T, Liu H, Estiu G et al. 2015. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature 520:683–87
    [Google Scholar]
  85. 85. 
    McLean KJ, Jacobs-Lorena M. 2017. Plasmodium falciparum Maf1 confers survival upon amino acid starvation. mBio 8:e02317–16
    [Google Scholar]
  86. 86. 
    Menard D, Dondorp A. 2017. Antimalarial drug resistance: a threat to malaria elimination. Cold Spring Harb. Perspect. Med. 7:a025619
    [Google Scholar]
  87. 87. 
    Menard D, Khim N, Beghain J, Adegnika AA, Shafiul-Alam M et al. 2016. A worldwide map of Plasmodium falciparum K13-propeller polymorphisms. N. Engl. J. Med. 374:2453–64
    [Google Scholar]
  88. 88. 
    Menard S, Ben Haddou T, Ramadani AP, Ariey F, Iriart X et al. 2015. Induction of multidrug tolerance in Plasmodium falciparum by extended artemisinin pressure. Emerg. Infect. Dis. 21:1733–41
    [Google Scholar]
  89. 89. 
    Miotto O, Amato R, Ashley EA, MacInnis B, Almagro-Garcia J et al. 2015. Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nat. Genet 47:226–34
    [Google Scholar]
  90. 90. 
    Miotto O, Sekihara M, Tachibana S-I, Yamauchi M, Pearson RD et al. 2019. Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea. bioRxiv 621813
  91. 91. 
    Mok S, Ashley EA, Ferreira PE, Zhu L, Lin Z et al. 2015. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science 347:431–35
    [Google Scholar]
  92. 92. 
    Mukherjee A, Bopp S, Magistrado P, Wong W, Daniels R et al. 2017. Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia. Malar. J. 16:195
    [Google Scholar]
  93. 93. 
    Mukherjee A, Gagnon D, Wirth DF, Richard D 2018. Inactivation of plasmepsins 2 and 3 sensitizes Plasmodium falciparum to the antimalarial drug piperaquine. Antimicrob. Agents Chemother. 62:e02309–17
    [Google Scholar]
  94. 94. 
    Nair S, Li X, Arya GA, McDew-White M, Ferrari M et al. 2018. Fitness costs and the rapid spread of kelch13-C580Y substitutions conferring artemisinin resistance. Antimicrob. Agents Chemother. 62:e00605–18
    [Google Scholar]
  95. 95. 
    Nakazawa S, Maoka T, Uemura H, Ito Y, Kanbara H 2002. Malaria parasites giving rise to recrudescence in vitro. Antimicrob. Agents Chemother. 46:958–65
    [Google Scholar]
  96. 96. 
    Ncokazi KK, Egan TJ. 2005. A colorimetric high-throughput β-hematin inhibition screening assay for use in the search for antimalarial compounds. Anal. Biochem. 338:306–19
    [Google Scholar]
  97. 97. 
    Noedl H, Se Y, Schaecher K, Smith BL, Socheat D et al. 2008. Evidence of artemisinin-resistant malaria in western Cambodia. N. Engl. J. Med. 359:2619–20
    [Google Scholar]
  98. 98. 
    Nsobya SL, Dokomajilar C, Joloba M, Dorsey G, Rosenthal PJ 2007. Resistance-mediating Plasmodium falciparum pfcrt and pfmdr1 alleles after treatment with artesunate-amodiaquine in Uganda. Antimicrob. Agents Chemother. 51:3023–25
    [Google Scholar]
  99. 99. 
    Ochong E, Tumwebaze PK, Byaruhanga O, Greenhouse B, Rosenthal PJ 2013. Fitness consequences of Plasmodium falciparum pfmdr1 polymorphisms inferred from ex vivo culture of Ugandan parasites. Antimicrob. Agents Chemother. 57:4245–51
    [Google Scholar]
  100. 100. 
    Olafson KN, Ketchum MA, Rimer JD, Vekilov PG 2015. Mechanisms of hematin crystallization and inhibition by the antimalarial drug chloroquine. PNAS 112:4946–51
    [Google Scholar]
  101. 101. 
    Packard RM. 2014. The origins of antimalarial-drug resistance. N. Engl. J. Med. 371:397–99
    [Google Scholar]
  102. 102. 
    Parobek CM, Parr JB, Brazeau NF, Lon C, Chaorattanakawee S et al. 2017. Partner-drug resistance and population substructuring of artemisinin-resistant Plasmodium falciparum in Cambodia. Genome Biol. Evol. 9:1673–86
    [Google Scholar]
  103. 103. 
    Patzewitz EM, Salcedo-Sora JE, Wong EH, Sethia S, Stocks PA et al. 2013. Glutathione transport: a new role for PfCRT in chloroquine resistance. Antioxid. Redox Signal. 19:683–95
    [Google Scholar]
  104. 104. 
    Peatey CL, Chavchich M, Chen N, Gresty KJ, Gray KA et al. 2015. Mitochondrial membrane potential in a small subset of artemisinin-induced dormant Plasmodium falciparum parasites in vitro. J. Infect. Dis. 212:426–34
    [Google Scholar]
  105. 105. 
    Pelleau S, Moss EL, Dhingra SK, Volney B, Casteras J et al. 2015. Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt. PNAS 112:11672–77
    [Google Scholar]
  106. 106. 
    Phuc BQ, Rasmussen C, Duong TT, Dong LT, Loi MA et al. 2017. Treatment failure of dihydroartemisinin/piperaquine for Plasmodium falciparum malaria, Vietnam. Emerg. Infect. Dis. 23:715–17
    [Google Scholar]
  107. 107. 
    Phyo AP, Ashley EA, Anderson TJC, Bozdech Z, Carrara VI et al. 2016. Declining efficacy of artemisinin combination therapy against P. falciparum malaria on the Thai-Myanmar border (2003–2013): the role of parasite genetic factors. Clin. Infect. Dis. 63:784–91
    [Google Scholar]
  108. 108. 
    Pulcini S, Staines HM, Lee AH, Shafik SH, Bouyer G et al. 2015. Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities. Sci. Rep. 5:14552
    [Google Scholar]
  109. 109. 
    Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF 2000. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403:906–9
    [Google Scholar]
  110. 110. 
    Rocamora F, Zhu L, Liong KY, Dondorp A, Miotto O et al. 2018. Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites. PLOS Pathog 14:e1006930
    [Google Scholar]
  111. 111. 
    Rohrbach P, Sanchez CP, Hayton K, Friedrich O, Patel J et al. 2006. Genetic linkage of pfmdr1 with food vacuolar solute import in Plasmodium falciparum. EMBO J 25:3000–11
    [Google Scholar]
  112. 112. 
    Roper C, Pearce R, Nair S, Sharp B, Nosten F, Anderson T 2004. Intercontinental spread of pyrimethamine-resistant malaria. Science 305:1124
    [Google Scholar]
  113. 113. 
    Rosenthal PJ. 2013. The interplay between drug resistance and fitness in malaria parasites. Mol. Microbiol. 89:1025–38
    [Google Scholar]
  114. 114. 
    Ross LS, Dhingra SK, Mok S, Yeo T, Wicht KJ et al. 2018. Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine. Nat. Commun. 9:3314
    [Google Scholar]
  115. 115. 
    Ross LS, Fidock DA. 2019. Elucidating mechanisms of drug-resistant Plasmodium falciparum. Cell Host Microbe 26:35–47
    [Google Scholar]
  116. 116. 
    Sa JM, Twu O, Hayton K, Reyes S, Fay MP et al. 2009. Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine. PNAS 106:18883–89
    [Google Scholar]
  117. 117. 
    Sanchez CP, Rohrbach P, McLean JE, Fidock DA, Stein WD, Lanzer M 2007. Differences in trans-stimulated chloroquine efflux kinetics are linked to PfCRT in Plasmodium falciparum. Mol. Microbiol 64:407–20
    [Google Scholar]
  118. 118. 
    Sanchez CP, Rotmann A, Stein WD, Lanzer M 2008. Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium falciparum. Mol. Microbiol 70:786–98
    [Google Scholar]
  119. 119. 
    Shaw PJ, Chaotheing S, Kaewprommal P, Piriyapongsa J, Wongsombat C et al. 2015. Plasmodium parasites mount an arrest response to dihydroartemisinin, as revealed by whole transcriptome shotgun sequencing (RNA-seq) and microarray study. BMC Genom 16:830
    [Google Scholar]
  120. 120. 
    Siddiqui G, Srivastava A, Russell AS, Creek DJ 2017. Multi-omics based identification of specific biochemical changes associated with PfKelch13-mutant artemisinin-resistant Plasmodium falciparum. J. Infect. Dis 215:1435–44
    [Google Scholar]
  121. 121. 
    Sidhu AB, Uhlemann AC, Valderramos SG, Valderramos JC, Krishna S, Fidock DA 2006. Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J. Infect. Dis. 194:528–35
    [Google Scholar]
  122. 122. 
    Sidhu AB, Verdier-Pinard D, Fidock DA 2002. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298:210–13
    [Google Scholar]
  123. 123. 
    Skinner-Adams TS, Fisher GM, Riches AG, Hutt OE, Jarvis KE et al. 2019. Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone. Commun. Biol. 2:166
    [Google Scholar]
  124. 124. 
    Small-Saunders JL, Hagenah L, Fidock DA 2020. Turning the tide: targeting PfCRT to combat drug-resistant P. falciparum?. Nat. Rev. Microbiol. 18:261–62
    [Google Scholar]
  125. 125. 
    Spring MD, Lin JT, Manning JE, Vanachayangkul P, Somethy S et al. 2015. Dihydroartemisinin-piperaquine failure associated with a triple mutant including kelch13 C580Y in Cambodia: an observational cohort study. Lancet Infect. Dis. 15:683–91
    [Google Scholar]
  126. 126. 
    St. Laurent B, Miller B, Burton TA, Amaratunga C, Men S et al. 2015. Artemisinin-resistant Plasmodium falciparum clinical isolates can infect diverse mosquito vectors of Southeast Asia and Africa. Nat. Commun. 6:8614
    [Google Scholar]
  127. 127. 
    Staines HM, Burrow R, Teo BH, Chis Ster I, Kremsner PG, Krishna S 2018. Clinical implications of Plasmodium resistance to atovaquone/proguanil: a systematic review and meta-analysis. J. Antimicrob. Chemother. 73:581–95
    [Google Scholar]
  128. 128. 
    Stokes BH, Yoo E, Murithi JM, Luth MR, Afanasyev P et al. 2019. Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents. PLOS Pathog 15:e1007722
    [Google Scholar]
  129. 129. 
    Straimer J, Gnadig NF, Stokes BH, Ehrenberger M, Crane AA, Fidock DA 2017. Plasmodium falciparum K13 mutations differentially impact ozonide susceptibility and parasite fitness in vitro. mBio 8:e00172-17
    [Google Scholar]
  130. 130. 
    Straimer J, Gnadig NF, Witkowski B, Amaratunga C, Duru V et al. 2015. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science 347:428–31
    [Google Scholar]
  131. 131. 
    Sullivan DJ. 2002. Theories on malarial pigment formation and quinoline action. Int. J. Parasitol. 32:1645–53
    [Google Scholar]
  132. 132. 
    Sullivan DJ. 2013. Plasmodium drug targets outside the genetic control of the parasite. Curr. Pharm. Des. 19:282–89
    [Google Scholar]
  133. 133. 
    Sutherland CJ, Lansdell P, Sanders M, Muwanguzi J, van Schalkwyk DA et al. 2017. pfk13-independent treatment failure in four imported cases of Plasmodium falciparum malaria treated with artemether-lumefantrine in the United Kingdom. Antimicrob. Agents Chemother. 61:e02382-16
    [Google Scholar]
  134. 134. 
    Tacoli C, Gai PP, Bayingana C, Sifft K, Geus D et al. 2016. Artemisinin resistance-associated K13 polymorphisms of Plasmodium falciparum in Southern Rwanda, 2010–2015. Am. J. Trop. Med. Hyg. 95:1090–93
    [Google Scholar]
  135. 135. 
    Takala-Harrison S, Clark TG, Jacob CG, Cummings MP, Miotto O et al. 2013. Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia. PNAS 110:240–45
    [Google Scholar]
  136. 136. 
    Takala-Harrison S, Jacob CG, Arze C, Cummings MP, Silva JC et al. 2015. Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. J. Infect. Dis. 211:670–79
    [Google Scholar]
  137. 137. 
    Teuscher F, Gatton ML, Chen N, Peters J, Kyle DE, Cheng Q 2010. Artemisinin-induced dormancy in Plasmodium falciparum: duration, recovery rates, and implications in treatment failure. J. Infect. Dis. 202:1362–68
    [Google Scholar]
  138. 138. 
    Thapar MM, Gil JP, Bjorkman A 2005. In vitro recrudescence of Plasmodium falciparum parasites suppressed to dormant state by atovaquone alone and in combination with proguanil. Trans. R. Soc. Trop. Med. Hyg. 99:62–70
    [Google Scholar]
  139. 139. 
    Tu Y. 2016. Artemisinin—a gift from traditional Chinese medicine to the world (Nobel lecture). Angew. Chem. Int. Ed. Engl. 55:10210–26
    [Google Scholar]
  140. 139a. 
    Uwimana A, Legrand E, Stokes BH, Ndikumana J-LM, Warsame Met al 2020. Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum Kelch13 R561H mutant parasites in Rwanda. Nat. Med In press
    [Google Scholar]
  141. 140. 
    Valderramos SG, Valderramos JC, Musset L, Purcell LA, Mercereau-Puijalon O et al. 2010. Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum. PLOS Pathog 6:e1000887
    [Google Scholar]
  142. 141. 
    van Biljon R, Niemand J, van Wyk R, Clark K, Verlinden B et al. 2018. Inducing controlled cell cycle arrest and re-entry during asexual proliferation of Plasmodium falciparum malaria parasites. Sci. Rep. 8:16581
    [Google Scholar]
  143. 142. 
    van der Pluijm RW, Imwong M, Chau NH, Hoa NT, Thuy-Nhien NT et al. 2019. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet Infect. Dis. 19:952–61
    [Google Scholar]
  144. 143. 
    van der Pluijm RW, Tripura R, Hoglund RM, Pyae Phyo A, Lek D et al. 2020. Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial. Lancet 395:1345–60
    [Google Scholar]
  145. 144. 
    Veiga MI, Dhingra SK, Henrich PP, Straimer J, Gnadig N et al. 2016. Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies. Nat. Commun. 7:11553
    [Google Scholar]
  146. 145. 
    Venkatesan M, Gadalla NB, Stepniewska K, Dahal P, Nsanzabana C et al. 2014. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine. Am. J. Trop. Med. Hyg. 91:833–43
    [Google Scholar]
  147. 146. 
    von Seidlein L, Peto TJ, Landier J, Nguyen TN, Tripura R et al. 2019. The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomised trial. PLOS Med 16:e1002745
    [Google Scholar]
  148. 147. 
    Wang J, Huang L, Li J, Fan Q, Long Y et al. 2010. Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation. PLOS ONE 5:e9582
    [Google Scholar]
  149. 148. 
    Wang J, Zhang CJ, Chia WN, Loh CC, Li Z et al. 2015. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.Nat. Commun 6:10111
    [Google Scholar]
  150. 149. 
    Wang Z, Cabrera M, Yang J, Yuan L, Gupta B et al. 2016. Genome-wide association analysis identifies genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum from China-Myanmar border. Sci. Rep. 6:33891
    [Google Scholar]
  151. 150. 
    Wellems TE, Plowe CV. 2001. Chloroquine-resistant malaria. J. Infect. Dis. 184:770–76
    [Google Scholar]
  152. 151. 
    White NJ. 2004. Antimalarial drug resistance. J. Clin. Investig. 113:1084–92
    [Google Scholar]
  153. 152. 
    White NJ. 2011. The parasite clearance curve. Malar. J. 10:278
    [Google Scholar]
  154. 153. 
    White NJ, Pukrittayakamee S, Hien TT, Faiz MA, Mokuolu OA, Dondorp AM 2014. Malaria. Lancet 383:723–35
    [Google Scholar]
  155. 154. 
    Witkowski B, Amaratunga C, Khim N, Sreng S, Chim P et al. 2013. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies. Lancet Infect. Dis. 13:1043–49
    [Google Scholar]
  156. 155. 
    Witkowski B, Duru V, Khim N, Ross LS, Saintpierre B et al. 2017. A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study. Lancet Infect. Dis. 17:174–83
    [Google Scholar]
  157. 156. 
    Witkowski B, Lelievre J, Barragan MJ, Laurent V, Su XZ et al. 2010. Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism. Antimicrob. Agents Chemother. 54:1872–77
    [Google Scholar]
  158. 157. 
    World Health Organ 2019. World malaria report 2019 Rep., World Health Organ. Geneva: https://www.who.int/publications-detail/world-malaria-report-2019
    [Google Scholar]
  159. 158. 
    WWARN K13 Genotype-Phenotype Study Group 2019. Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments—a WWARN individual patient data meta-analysis. BMC Med 17:1
    [Google Scholar]
  160. 159. 
    Xie SC, Dogovski C, Hanssen E, Chiu F, Yang T et al. 2016. Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins. J. Cell Sci. 129:406–16
    [Google Scholar]
  161. 160. 
    Yang T, Yeoh LM, Tutor MV, Dixon MW, McMillan PJ et al. 2019. Decreased K13 abundance reduces hemoglobin catabolism and proteotoxic stress, underpinning artemisinin resistance. Cell Rep 29:2917–28.e5
    [Google Scholar]
  162. 161. 
    Zhan W, Visone J, Ouellette T, Harris JC, Wang R et al. 2019. Improvement of asparagine ethylenediamines as anti-malarial Plasmodium-selective proteasome inhibitors. J. Med. Chem. 62:6137–45
    [Google Scholar]
  163. 162. 
    Zhang H, Howard EM, Roepe PD 2002. Analysis of the antimalarial drug resistance protein PfCRT expressed in yeast. J. Biol. Chem. 277:49767–75
    [Google Scholar]
  164. 163. 
    Zhang J, Li N, Siddiqui FA, Xu S, Geng J et al. 2019. In vitro susceptibility of Plasmodium falciparum isolates from the China-Myanmar border area to artemisinins and correlation with K13 mutations. Int. J. Parasitol. Drugs Drug Resist. 10:20–27
    [Google Scholar]
  165. 164. 
    Zhang M, Gallego-Delgado J, Fernandez-Arias C, Waters NC, Rodriguez A et al. 2017. Inhibiting the Plasmodium eIF2α kinase PK4 prevents artemisinin-induced latency. Cell Host Microbe 22:766–76.e4
    [Google Scholar]
  166. 165. 
    Zhang M, Wang C, Otto TD, Oberstaller J, Liao X et al. 2018. Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis. Science 360:eaap7847
    [Google Scholar]
  167. 166. 
    Zhu L, Tripathi J, Rocamora FM, Miotto O, van der Pluijm R et al. 2018. The origins of malaria artemisinin resistance defined by a genetic and transcriptomic background. Nat. Commun. 9:5158
    [Google Scholar]
/content/journals/10.1146/annurev-micro-020518-115546
Loading
/content/journals/10.1146/annurev-micro-020518-115546
Loading

Data & Media loading...

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error