Emergence of resistance to atovaquone-proguanil in malaria parasites: Insights from computational modeling and clinical case reports

Antimicrobial Agents and Chemotherapy

Volumn 58, Issue 8, 2014, Pages 4504-4514

  Cottrell, Gilles ^a,b   Musset, Lise ^c,d   Hubert, Véronique ^e   Le Bras, Jacques ^a,b,e   Clain, Jérôme ^a,b,e  

^a INSTITUT DE RECHERCHE POUR LE DÉVELOPPEMENT   (France)

^b UNIVERSITÉ PARIS DESCARTES   (France)

^c INSTITUT PASTEUR DE LA GUYANE   (French Guiana)

^d Centre National de Référence du Paludisme Laboratoire Associé pour la Région Antilles Guyane   (French Guiana)

^e BICHAT HOSPITAL   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIMALARIAL AGENT; ATOVAQUONE; ATOVAQUONE, PROGUANIL DRUG COMBINATION; DRUG COMBINATION; MITOCHONDRIAL DNA; PROGUANIL;

ADOLESCENT; BLOOD; CHILD; DRUG COMBINATION; DRUG EFFECTS; DRUG RESISTANCE; ERYTHROCYTE; FEMALE; GENETICS; GROWTH, DEVELOPMENT AND AGING; HUMAN; INFANT; LIFE CYCLE STAGE; MALARIA, FALCIPARUM; MALE; METABOLISM; MIDDLE AGED; MITOCHONDRIAL GENOME; MITOCHONDRION; MUTATION; PARASITOLOGY; PLASMODIUM FALCIPARUM; STATISTICAL MODEL; TREATMENT FAILURE; YOUNG ADULT;

ADOLESCENT; ANTIMALARIALS; ATOVAQUONE; CHILD; DNA, MITOCHONDRIAL; DRUG COMBINATIONS; DRUG RESISTANCE; ERYTHROCYTES; FEMALE; GENOME, MITOCHONDRIAL; HUMANS; INFANT; LIFE CYCLE STAGES; MALARIA, FALCIPARUM; MALE; MIDDLE AGED; MITOCHONDRIA; MODELS, STATISTICAL; MUTATION; PLASMODIUM FALCIPARUM; PROGUANIL; TREATMENT FAILURE; YOUNG ADULT;

EID: 84905401074     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.02550-13     Document Type: Article

References (73)

1. Read AF, Day T, Huijben S. 2011. The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy. Proc. Natl. Acad. Sci. U. S. A. 108(Suppl 2):S10871-S10877. http://dx.doi.org/10.1073/pnas.1100299108.
2. Bloland PB, Kazembe PN, Watkins WM, Doumbo OK, Nwanyanwu OC, Ruebush TK, II. 1997. Malarone-donation programme in Africa. Lancet 350:1624-1625. http://dx.doi.org/10.1016/S0140-6736 (97) 06082-0.
3. Nosten F. 2000. Prophylactic effect of Malarone against malaria: all good news? Lancet 356:1864-1865. http://dx.doi.org/10.1016/S0140-6736 (00) 03250-5.
4. Hoyer S, Nguon S, Kim S, Habib N, Khim N, Sum S, Christophel EM, Bjorge S, Thomson A, Kheng S, Chea N, Yok S, Top-Ros SS, Sophal U, Thompson MM, Mellor S, Ariey F, Witkowski B, Yeang C, Yeung S, Duong S, Newman RD, Menard D. 2012. Focused screening and treatment (FSAT): a PCR-based strategy to detect malaria parasite carriers and contain drug resistant P. falciparum, Pailin, Cambodia. PLoS One 7:e45797. http://dx.doi.org/10.1371/journal.pone.0045797.
5. Nixon GL, Moss DM, Shone AE, Lalloo DG, Fisher N, O'Neill PM, Ward SA, Biagini GA. 2013. Antimalarial pharmacology and therapeutics of atovaquone. J. Antimicrob. Chemother. 68:977-985. http://dx.doi.org/10.1093/jac/dks504.
6. Looareesuwan S, Viravan C, Webster HK, Kyle DE, Hutchinson DB, Canfield CJ. 1996. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am. J. Trop. Med. Hyg. 54:62-66.
7. Srivastava IK, Rottenberg H, Vaidya AB. 1997. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. J. Biol. Chem. 272:3961-3966. http://dx.doi.org/10.1074/jbc. 272.7.3961.
8. Srivastava IK, Vaidya AB. 1999. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob. Agents Chemother. 43:1334-1339.
9. Peterson DS, Milhous WK, Wellems TE. 1990. Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria. Proc. Natl. Acad. Sci. U. S. A. 87:3018-3022. http://dx.doi.org/10.1073/pnas.87.8.3018.
10. Foote SJ, Galatis D, Cowman AF. 1990. Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proc. Natl. Acad. Sci. U. S. A. 87:3014-3017. http://dx.doi.org/10.1073/pnas.87. 8.3014.
11. Korsinczky M, Chen N, Kotecka B, Saul A, Rieckmann K, Cheng Q. 2000. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob. Agents Chemother. 44:2100-2108. http://dx.doi.org/10.1128/AAC.44.8.2100-2108. 2000.
12. Kessl JJ, Ha KH, Merritt AK, Lange BB, Hill P, Meunier B, Meshnick SR, Trumpower BL. 2005. Cytochrome b mutations that modify the ubiquinol-binding pocket of the cytochrome bc1 complex and confer antimalarial drug resistance in Saccharomyces cerevisiae. J. Biol. Chem. 280:17142-17148. http://dx.doi.org/10. 1074/jbc. M500388200.
13. Sirawaraporn W, Sathitkul T, Sirawaraporn R, Yuthavong Y, Santi DV. 1997. Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc. Natl. Acad. Sci. U. S. A. 94:1124-1129. http://dx.doi.org/10.1073/pnas.94. 4.1124.
14. Basco LK, Ringwald P. 2000. Molecular epidemiology of malaria in Yaounde, Cameroon. VI. Sequence variations in the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene and in vitro resistance to pyrimethamine and cycloguanil. Am. J. Trop. Med. Hyg. 62:271-276.
15. Naidoo I, Roper C. 2013. Mapping 'partially resistant', 'fully resistant', and 'super resistant' malaria. Trends Parasitol. 29:505-515. http://dx.doi.org/10.1016/j.pt.2013.08.002.
16. Musset L, Pradines B, Parzy D, Durand R, Bigot P, Le Bras J. 2006. Apparent absence of atovaquone/proguanil resistance in 477 Plasmodium falciparum isolates from untreated French travelers. J. Antimicrob. Chemother. 57:110-115. http://dx.doi.org/10.1093/jac/dki420.
17. Ekala MT, Khim N, Legrand E, Randrianarivelojosia M, Jambou R, Fandeur T, Menard D, Assi SB, Henry MC, Rogier C, Bouchier C, Mercereau-Puijalon O. 2007. Sequence analysis of Plasmodium falciparum cytochrome b in multiple geographic sites. Malar. J. 6:164. http://dx.doi.org/10.1186/1475-2875-6-164.
18. Tanabe K, Jombart T, Horibe S, Palacpac NM, Honma H, Tachibana S, Nakamura M, Horii T, Kishino H, Mita T. 2013. Plasmodium falciparum mitochondrial genetic diversity exhibits isolation-by-distance patterns supporting a sub-Saharan African origin. Mitochondrion 13:630-636. http://dx.doi.org/10.1016/j.mito.2013.08.008.
19. Sutherland CJ, Laundy M, Price N, Burke M, Fivelman QL, Pasvol G, Klein JL, Chiodini PL. 2008. Mutations in the Plasmodium falciparum cytochrome b gene are associated with delayed parasite recrudescence in malaria patients treated with atovaquone-proguanil. Malar. J. 7:240. http://dx.doi.org/10.1186/1475-2875- 7-240.
20. Schwartz E, Bujanover S, Kain KC. 2003. Genetic confirmation of atovaquoneproguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa. Clin. Infect. Dis. 37:450-451. http://dx.doi.org/10.1086/375599.
21. Musset L, Bouchaud O, Matheron S, Massias L, Le Bras J. 2006. Clinical atovaquone-proguanil resistance of Plasmodium falciparum associated with cytochrome b codon 268 mutations. Microbes Infect. 8:2599-2604. http://dx.doi.org/10.1016/j.micinf.2006.07.011.
22. Musset L, Le Bras J, Clain J. 2007. Parallel evolution of adaptive mutations in Plasmodium falciparum mitochondrial DNA during atovaquoneproguanil treatment. Mol. Biol. Evol. 24:1582-1585. http://dx.doi.org/10.1093/molbev/ msm087.
23. Srivastava IK, Morrisey JM, Darrouzet E, Daldal F, Vaidya AB. 1999. Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites. Mol. Microbiol. 33:704-711. http://dx.doi.org/10.1046/j.1365- 2958.1999.01515.x.
24. Preiser PR, Wilson RJ, Moore PW, McCready S, Hajibagheri MA, Blight KJ, Strath M, Williamson DH. 1996. Recombination associated with replication of malarial mitochondrial DNA. EMBO J. 15:684-693.
25. Birky CW, Jr. 1994. Relaxed and stringent genomes: why cytoplasmic genes don't obey Mendel's laws. J. Hered. 85:355-365.
26. Hastings IM. 2004. The origins of antimalarial drug resistance. Trends Parasitol. 20:512-518. http://dx.doi.org/10.1016/j.pt.2004.08.006.
27. Van Dooren GG, Marti M, Tonkin CJ, Stimmler LM, Cowman AF, McFadden GI. 2005. Development of the endoplasmic reticulum, mitochondrion and apicoplast during the asexual life cycle of Plasmodium falciparum. Mol. Microbiol. 57:405-419. http://dx.doi.org/10.1111/j.1365-2958.2005.04699.x.
28. Coller HA, Khrapko K, Bodyak ND, Nekhaeva E, Herrero-Jimenez P, Thilly WG. 2001. High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nat. Genet. 28:147-150. http://dx.doi.org/10.1038/88859.
29. Slomianny C, Prensier G. 1986. Application of the serial sectioning and tridimensional reconstruction techniques to the morphological study of the Plasmodium falciparum mitochondrion. J. Parasitol. 72:595-598. http://dx.doi.org/10.2307/3281516.
30. Peters JM, Chen N, Gatton M, Korsinczky M, Fowler EV, Manzetti S, Saul A, Cheng Q. 2002. Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in Plasmodium falciparum. Antimicrob. Agents Chemother. 46:2435-2441. http://dx.doi.org/10.1128/AAC.46.8.2435-2441.2002.
31. Fisher N, Abd Majid R, Antoine T, Al-Helal M, Warman AJ, Johnson DJ, Lawrenson AS, Ranson H, O'Neill PM, Ward SA, Biagini GA. 2012. Cytochrome b mutation Y268S conferring atovaquone resistance phenotype in malaria parasite results in reduced parasite bc1 catalytic turnover and protein expression. J. Biol. Chem. 287:9731-9741. http://dx.doi.org/10.1074/jbc. M111.324319.
32. Lynch M, Sung W, Morris K, Coffey N, Landry CR, Dopman EB, Dickinson WJ, Okamoto K, Kulkarni S, Hartl DL, Thomas WK. 2008. A genome-wide view of the spectrum of spontaneous mutations in yeast. Proc. Natl. Acad. Sci. U. S. A. 105:9272-9277. http://dx.doi.org/10.1073/pnas.0803466105.
33. Haag-Liautard C, Coffey N, Houle D, Lynch M, Charlesworth B, Keightley PD. 2008. Direct estimation of the mitochondrial DNA mutation rate in Drosophila melanogaster. PLoS Biol. 6:e204. http://dx.doi.org/10.1371/journal.pbio. 0060204.
34. Saxer G, Havlak P, Fox SA, Quance MA, Gupta S, Fofanov Y, Strassmann JE, Queller DC. 2012. Whole genome sequencing of mutation accumulation lines reveals a low mutation rate in the social amoeba Dictyostelium discoideum. PLoS One 7:e46759. http://dx.doi.org/10.1371/journal.pone.0046759.
35. Sung W, Tucker AE, Doak TG, Choi E, Thomas WK, Lynch M. 2012. Extraordinary genome stability in the ciliate Paramecium tetraurelia. Proc. Natl. Acad. Sci. U. S. A. 109:19339-19344. http://dx.doi.org/10.1073/pnas. 1210663109.
36. Bopp SE, Manary MJ, Bright AT, Johnston GL, Dharia NV, Luna FL, McCormack S, Plouffe D, McNamara CW, Walker JR, Fidock DA, Denchi EL, Winzeler EA. 2013. Mitotic evolution of Plasmodium falciparum shows a stable core genome but recombination in antigen families. PLoS Genet. 9:e1003293. http://dx.doi.org/10. 1371/journal.pgen. 1003293.
37. Roestenberg M, O'Hara GA, Duncan CJ, Epstein JE, Edwards NJ, Scholzen A, Van Der Ven AJ, Hermsen CC, Hill AV, Sauerwein RW. 2012. Comparison of clinical and parasitological data from controlled human malaria infection trials. PLoS One 7:e38434. http://dx.doi.org/10.1371/journal.pone.0038434.
38. Briand V, Bouchaud O, Tourret J, Behr C, Abgrall S, Ralaimazava P, Le Bras J, Fontanet A. 2007. Hospitalization criteria in imported falciparum malaria. J. Travel Med. 14:306-311. http://dx.doi.org/10.1111/j.1708-8305.2007. 00143.x.
39. Maiga-Ascofare O, Le Bras J, Mazmouz R, Renard E, Falcao S, Broussier E, Bustos D, Randrianarivelojosia M, Omar SA, Aubouy A, Lepere JF, Jean-Francois V, Djimde AA, Clain J. 2010. Adaptive differentiation of Plasmodium falciparum populations inferred from single-nucleotide polymorphisms (SNPs) conferring drug resistance and from neutral SNPs. J. Infect. Dis. 202:1095-1103. http://dx.doi.org/10.1086/656142.
40. White NJ. 2002. The assessment of antimalarial drug efficacy. Trends Parasitol. 18:458-464. http://dx.doi.org/10.1016/S1471-4922 (02) 02373-5.
41. White NJ. 1997. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob. Agents Chemother. 41:1413-1422.
42. White NJ. 2013. Pharmacokinetic and pharmacodynamic considerations in antimalarial dose optimization. Antimicrob. Agents Chemother. 57:5792-5807. http://dx.doi.org/10.1128/AAC.00287-13.
43. Chiodini PL, Conlon CP, Hutchinson DB, Farquhar JA, Hall AP, Peto TE, Birley H, Warrell DA. 1995. Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria. J. Antimicrob. Chemother. 36:1073-1078. http://dx.doi.org/10.1093/jac/36.6.1073.
44. Kuhn S, Gill MJ, Kain KC. 2005. Emergence of atovaquone-proguanil resistance during treatment of Plasmodium falciparum malaria acquired by a non-immune north American traveler to west Africa. Am. J. Trop. Med. Hyg. 72:407-409.
45. Savini H, Bogreau H, Bertaux L, Bouchiba H, Kraemer P, Parzy D, Garnotel E, Rogier C, Simon F, Pradines B. 2008. First case of emergence of atovaquone-proguanil resistance in Plasmodium falciparum during treatment in a traveler in Comoros. Antimicrob. Agents Chemother. 52:2283-2284. http://dx.doi.org/10.1128/AAC.00282-08.
46. Schmitt MW, Kennedy SR, Salk JJ, Fox EJ, Hiatt JB, Loeb LA. 2012. Detection of ultra-rare mutations by next-generation sequencing. Proc. Natl. Acad. Sci. U. S. A. 109:14508-14513. http://dx.doi.org/10.1073/pnas.1208715109.
47. Kennedy SR, Salk JJ, Schmitt MW, Loeb LA. 2013. Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet. 9:e1003794. http://dx.doi.org/10.1371/journal.pgen. 1003794.
48. Ford CB, Shah RR, Maeda MK, Gagneux S, Murray MB, Cohen T, Johnston JC, Gardy J, Lipsitch M, Fortune SM. 2013. Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis. Nat. Genet. 45:784-790. http://dx.doi.org/10.1038/ng.2656.
49. Colijn C, Cohen T, Ganesh A, Murray M. 2011. Spontaneous emergence of multiple drug resistance in tuberculosis before and during therapy. PLoS One 6:e18327. http://dx.doi.org/10.1371/journal.pone.0018327.
50. Pennings PS. 2012. Standing genetic variation and the evolution of drug resistance in HIV. PLoS Comput. Biol. 8:e1002527. http://dx.doi.org/10.1371/ journal.pcbi.1002527.
51. White NJ, Pongtavornpinyo W. 2003. The de novo selection of drugresistant malaria parasites. Proc. Biol. Sci. 270:545-554. http://dx.doi.org/10.1098/ rspb.2002.2241.
52. McCarthy JS, Sekuloski S, Griffin PM, Elliott S, Douglas N, Peatey C, Rockett R, O'Rourke P, Marquart L, Hermsen C, Duparc S, Mohrle J, Trenholme KR, Humberstone AJ. 2011. A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs. PLoS One 6:e21914. http://dx.doi.org/10.1371/journal.pone. 0021914.
53. Fry M, Pudney M. 1992. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4'-chlorophenyl) cyclohexyl]-3-hydroxy-1, 4-naphthoquinone (566C80). Biochem. Pharmacol. 43:1545-1553. http://dx.doi.org/10.1016/0006-2952 (92) 90213-3.
54. Roepe PD. 2014. To kill or not to kill, that is the question: cytocidal antimalarial drug resistance. Trends Parasitol. 30:130-135. http://dx.doi.org/ 10.1016/j.pt.2014.01.004.
55. Hussein Z, Eaves CJ, Hutchinson DB, Canfield CJ. 1996. Population pharmacokinetics of proguanil in patients with acute Plasmodium falciparum malaria after combined therapy with atovaquone. Br. J. Clin. Pharmacol. 42:589-597. http://dx.doi.org/10.1111/j.1365-2125.1996.tb00053.x.
56. Hussein Z, Eaves J, Hutchinson DB, Canfield CJ. 1997. Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum. Clin. Pharmacol. Ther. 61:518-530. http://dx.doi.org/10. 1016/S0009-9236 (97) 90132-6.
57. White NJ, Pongtavornpinyo W, Maude RJ, Saralamba S, Aguas R, Stepniewska K, Lee SJ, Dondorp AM, White LJ, Day NP. 2009. Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance. Malar. J. 8:253. http://dx.doi.org/10.1186/1475-2875-8-253.
58. Fivelman QL, Butcher GA, Adagu IS, Warhurst DC, Pasvol G. 2002. Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria. Malar. J. 1:1. http://dx.doi.org/10. 1186/1475-2875-1-1.
59. Perry TL, Pandey P, Grant JM, Kain KC. 2009. Severe atovaquoneresistant Plasmodium falciparum malaria in a Canadian traveler returned from the Indian subcontinent. Open Med. 3:e10-e16.
60. Rose GW, Suh KN, Kain KC, Le Saux N, McCarthy AE. 2008. Atovaquoneproguanil resistance in imported falciparum malaria in a young child. Pediatr. Infect. Dis. J. 27:567-569. http://dx.doi.org/10.1097/INF. 0b013e318167918d.
61. Roberts CH, Armstrong M, Zatyka E, Boadi S, Warren S, Chiodini PL, Sutherland CJ, Doherty T. 2013. Gametocyte carriage in Plasmodium falciparum-infected travellers. Malar. J. 12:31. http://dx.doi.org/10.1186/1475- 2875-12-31.
62. Rathod PK, McErlean T, Lee PC. 1997. Variations in frequencies of drug resistance in Plasmodium falciparum. Proc. Natl. Acad. Sci. U. S. A. 94:9389-9393. http://dx.doi.org/10.1073/pnas.94.17.9389.
63. Pongtavornpinyo W, Hastings IM, Dondorp A, White LJ, Maude RJ, Saralamba S, Day NP, White NJ, Boni MF. 2009. Probability of emergence of antimalarial resistance in different stages of the parasite life cycle. Evol. Appl. 2:52-61. http://dx.doi.org/10.1111/j.1752-4571.2008.00067.x.
64. Johnston GL, Smith DL, Fidock DA. 2013. Malaria's missing number: calculating the human component of R0 by a within-host mechanistic model of Plasmodium falciparum infection and transmission. PLoS Comput. Biol. 9:e1003025. http://dx.doi.org/10.1371/journal.pcbi.1003025.
65. Dong CK, Urgaonkar S, Cortese JF, Gamo FJ, Garcia-Bustos JF, Lafuente MJ, Patel V, Ross L, Coleman BI, Derbyshire ER, Clish CB, Serrano AE, Cromwell M, Barker RH, Jr, Dvorin JD, Duraisingh MT, Wirth DF, Clardy J, Mazitschek R. 2011. Identification and validation of tetracyclic benzothiazepines as Plasmodium falciparum cytochrome bc1 inhibitors. Chem. Biol. 18:1602-1610. http://dx.doi.org/10.1016/j.chembiol.2011.09.016.
66. Nam TG, McNamara CW, Bopp S, Dharia NV, Meister S, Bonamy GM, Plouffe DM, Kato N, McCormack S, Bursulaya B, Ke H, Vaidya AB, Schultz PG, Winzeler EA. 2011. A chemical genomic analysis of decoquinate, a Plasmodium falciparum cytochrome b inhibitor. ACS Chem. Biol. 6:1214-1222. http://dx.doi.org/10.1021/ cb200105d.
67. Biagini GA, Fisher N, Shone AE, Mubaraki MA, Srivastava A, Hill A, Antoine T, Warman AJ, Davies J, Pidathala C, Amewu RK, Leung SC, Sharma R, Gibbons P, Hong DW, Pacorel B, Lawrenson AS, Charoensutthivarakul S, Taylor L, Berger O, Mbekeani A, Stocks PA, Nixon GL, Chadwick J, Hemingway J, Delves MJ, Sinden RE, Zeeman AM, Kocken CH, Berry NG, O'Neill PM, Ward SA. 2012. Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria. Proc. Natl. Acad. Sci. U. S. A. 109:8298-8303. http://dx.doi.org/10.1073/pnas.1205651109.
68. Nilsen A, La Crue AN, White KL, Forquer IP, Cross RM, Marfurt J, Mather MW, Delves MJ, Shackleford DM, Saenz FE, Morrisey JM, Steuten J, Mutka T, Li Y, Wirjanata G, Ryan E, Duffy S, Kelly JX, Sebayang BF, Zeeman AM, Noviyanti R, Sinden RE, Kocken CH, Price RN, Avery VM, Angulo-Barturen I, Jimenez-Diaz MB, Ferrer S, Herreros E, Sanz LM, Gamo FJ, Bathurst I, Burrows JN, Siegl P, Guy RK, Winter RW, Vaidya AB, Charman SA, Kyle DE, Manetsch R, Riscoe MK. 2013. Quinolone-3-diarylethers: a new class of antimalarial drug. Sci. Transl. Med. 5:177ra37. http://dx.doi.org/10.1126/scitranslmed.3005029.
69. Backer JS, Birky CW, Jr. 1985. The origin of mutant cells: mechanisms by which Saccharomyces cerevisiae produces cells homoplasmic for new mitochondrial mutations. Curr. Genet. 9:627-640. http://dx.doi.org/10.1007/BF00449815.
70. Huijben S, Bell AS, Sim DG, Tomasello D, Mideo N, Day T, Read AF. 2013. Aggressive chemotherapy and the selection of drug-resistant pathogens. PLoS Pathog. 9:e1003578. http://dx.doi.org/10.1371/journal.ppat.1003578.
71. Van Vugt M, Leonardi E, Phaipun L, Slight T, Thway KL, McGready R, Brockman A, Villegas L, Looareesuwan S, White NJ, Nosten F. 2002. Treatment of uncomplicated multidrug-resistant falciparum malaria with artesunate-atovaquone- proguanil. Clin. Infect. Dis. 35:1498-1504. http://dx.doi.org/10.1086/344901.
72. McGready R, Keo NK, Villegas L, White NJ, Looareesuwan S, Nosten F. 2003. Artesunate-atovaquone-proguanil rescue treatment of multidrugresistant Plasmodium falciparum malaria in pregnancy: a preliminary report. Trans. R. Soc. Trop. Med. Hyg. 97:592-594. http://dx.doi.org/10.1016/S0035-9203 (03) 80040-8.
73. McGready R, Ashley EA, Moo E, Cho T, Barends M, Hutagalung R, Looareesuwan S, White NJ, Nosten F. 2005. A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy. J. Infect. Dis. 192:846-853. http://dx.doi.org/10.1086/432551.