Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
To purchase hard copies of this book, please contact the representative in India:
CBS Publishers & Distributors Pvt. Ltd.
www.cbspd.com
|
customercare@cbspd.com
The use of molecular markers of resistance to monitor the emergence, and the spread of parasite resistance to antimalarial drugs is a very effective way of monitoring antimalarial drug resistance. The identification and validation of molecular markers have boosted our confidence in using these tools to monitor resistance. For example, P. falciparum chloroquine resistance transporter (PfCRT), P. falciparum multidrug resistance protein 1 (PfMDR1), P. falciparum multidrug kelch 13 (pfk13), have been identified as molecular markers of resistance to chloroquine, lumefantrine, and artemisinin respectively. The mechanism of resistance to antimalarial drugs is mostly by; (1) undergoing mutations in the parasite genome, leading to expelling the drug from the digestive vacuole, or (2) loss of binding affinity between the drug and its target. Increased copy number in the pfmdr1 gene also leads to resistance to antimalarial drugs. The major cause of the widespread chloroquine and sulfadoxine-pyrimethamine resistance globally is the spread of parasites resistant to these drugs from Southeast Asia to Africa, the Pacific, and South America. Only a few mutations in the parasite genome lead to resistance to chloroquine and sulfadoxine-pyrimethamine arising from indigenous parasites in Africa, Pacific, and South America.
West Africa Center for Cell Biology and Infectious Pathogen, University of Ghana, Accra, Ghana
*Address all correspondence to: peterhodoameda@gmail.com
1. Introduction
The monitoring and identification of drug-resistant P. falciparum strains is paramount to the fight against malaria. The traditional identification of resistant parasite strains is by in vivo and/or in vivo drug susceptibility assays. Although these methods are effective in identifying resistant strains, they are faced with an array of challenges. The most profound challenge being faced by both in vivo and in vitro techniques is the cost and time associated with them. Since malaria is mostly endemic in poor countries, it is imperative to identify cost-friendly methods for the surveillance and identification of resistant parasites.
One method that shows a lot of promise in the identification of resistant parasite strains is the use of polymerase chain reaction and sequencing techniques to identify the molecular markers of resistance that are associated with resistance to a particular antimalarial drug (s). The ever-improving knowledge in malaria parasite genomics has made it possible to identify mutations that are associated with resistance to antimalarial drugs. Identification of these markers in resistant strains and the validation of these markers using genome editing techniques such as Crispr-Cas9 have been possible, making us confident that, a parasite will be resistant to an antimalarial drug when the molecular marker of resistance-associated to it is identified in the parasite, without the performance of in vitro drug susceptibility assay. The use of molecular markers of resistance in identifying parasite-resistant strains has not just made it possible to identify resistant parasite strains, but also to predict how fast a resistant strain is emerging and how fast it is spreading. From the aforementioned advantages, it is clear that the most cost-friendly, time-saving, high through-put, and robust technique to use in identifying the emergence and spread of a resistance parasite strain by PCR and sequencing techniques to identify molecular markers of resistance to antimalarial drugs.
This chapter will focus on the Plasmodium parasite molecular markers of resistance responsible for antimalarial drug resistance. The mechanism of resistance due to mutations or increase in copy number in the molecular markers of resistance to the different antimalarial drugs will be elaborated. The epidemiology of different molecular markers will be also addressed.
2. Molecular markers of resistance to Quinoline-based drugs
2.1 P. falciparum chloroquine resistance transporter (pfcrt)
The P. falciparum Chloroquine Resistance Transporter (pfcrt) gene is a putative transporter, has a weight of 49 kDa, is a member of the drug transporter superfamily, and localized to the parasite digestive vacuole [1, 2]. Mutations within the pfcrt are the primary responsible for resistance to chloroquine. This was identified after a genetic cross experiment between CQ-sensitive HB3 and CQ-resistant Dd2 clones. Genetic analysis of the CQ-resistant progeny identified mutation in a single genetic locus on chromosome 7.A quantitative trait loci (QTL) analysis mapped a mutation on the 13-exon of the pfcrt gene [1, 3]. Studies by [4] have confirmed that mutation in the pfcrt gene is associated with chloroquine resistance in a genome-wide association study. A single mutation, resulting in the change in amino acid from K76T confers resistance to CQ in both labs adapted and field isolated P. falciparum strains. Removal of this mutation in CQ-resistant strains (Dd2 from Southeast Asia and 7G8 from South Africa) resulted in the total loss of resistance to chloroquine in these strains [5].
The mechanism of CQ resistance after the replacement of a positively charged lysine (K) with a neutral threonine (T) results in the expulsion of deprotonated CQ out of the digestive vacuole. The expulsion is achieved through either active transport or facilitated diffusion. This results in decreasing access of the CQ to heme, which is its target [6].
There are other mutations in the pfcrt gene which introduce different amino acids in the wild-type amino acids CVMNK, which compensates for the altered PfCRT function due to pfcrt K76T mutation and may subsequently modulate drug susceptibility in the parasite. These mutations occur in the surroundings of K76T (position 72–76). These mutations that occur at positions 72–76 may be unique to a particular geographic location. For example, the CVIET mutations at positions 72–76 are mostly found in parasites from Africa and Southeast Asia, while the SVMNT mutations at position 72–76 are found in South America, the Philippines, and Papua New Guinea [7].
The use of pfcrt K76T mutations in epidemiology surveillance does not only apply to chloroquine resistance but also some partner drugs used in artemisinin-based combination therapy. For example, the introduction of mutant pfcrt into CQ-sensitive GC03 strain resulted in reduced susceptibility to both amodiaquine and its primary metabolite desethylamodiaquine (DEAQ) [8]. Studies conducted by [9] using field isolates showed the selection of pfcrt K76T in AQ recrudescence treatment outcome. Parasite resistance to AQ or DEAQ is not solely dependent on pfcrt mutation, but rather a combination of mutation(s) in both the pfcrt and pfmdr1 gene [10].
The pfcrt K76T mutation does not only results in resistance to CQ and AQ but also results in increased susceptibility to lumefantrine [11], quinine, halofantrine, mefloquine, artemisinin and its derivatives [8, 12].
2.2 P. falciparum multidrug resistance protein 1
The P. falciparum multidrug resistance protein 1 (pfmdr1) is a member of the ATP-binding cassette (ABC). The pfmdr1 is also known as the P-glycoproteins homolog 1 (Pgh-1) [6]. The PfMDR1 is localized in the membrane of the DV. The PfMDR1 is a transporter and functions by regulating drug accumulation in the parasite’s DV [6].
The pfmdr1 plays a very important role in the parasite response to different antimalarial drugs. The two mechanisms used by the pfmdr1 gene to regulate antimalarial drug response are through increased pfmdr1 copy number or by introducing mutations in the gene. Increased copy number of pfmdr1 has been associated with reduced in vitro susceptibility to halofantrine, quinine, mefloquine, dihydroartemisinin, and artesunate [13]. Most importantly, increased pfmdr1 copy number in clinical isolates is the cause of mefloquine monotherapy [14] or artesunate-mefloquine combination treatment failures [15]. The validation of increased pfmdr1 copy number and its involvement in mefloquine, lumefantrine, halofantrine, quinine, and artemisinin resistance was proven in an experiment that involved the knockout of one of the two copies of drug-resistant FCB strains, resulting in the reversal of its resistance to make it susceptible to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin [16].
The polymorphisms which occur in different haplotypes of pfmdr1 result in resistance to different antimalarial drugs. These mutations alter the substrate specificity of pfmdr1 [17]. The pfmdr1 N86Y mutation has been associated with CQ and AQ treatment failure, although the association to CQ is weak [18]. The pfmdr1 D1246Y have been reported to be involved in resistance to AQ/DEAQ. In East Africa, the pfmdr1 86Y-184Y-1246Y haplotype was selected for an AQ recrudescence treatment outcome [19]. In other studies using field isolates from Columbia observed high AQ IC50 for parasites with pfmdr1 D1246Y [20]. The pfmdr1 N86-F184-D1246 haplotype is associated with resistance to lumefantrine in Africa [21, 22] whiles the pfmdr1 N1042D was associated with increased in vitro lumefantrine IC50 values in isolates from the Thai-Myanmar border [23]. The pfmdr1 S1034C/N1042D/D1246Y mutations are associated with reduced susceptibility to quinine [24]. The pfmdr1 and pfcrt alleles may interact to confer higher resistance to AQ and DEAQ [10].
2.3 P. falciparum multidrug resistance-associated protein (PfMRP)
The P. falciparum Multidrug Resistance-Associated Protein (pfmrp) belongs to the ABC transporter family [25]. The pfmrp acts as a transport regulatory protein. Mutations in the pfmrp have been associated with resistance to some antimalarial drugs such as quinine and chloroquine [25]. The Y191H and A437S have been shown to have a weak association to CQ-resistance in Asia and the Americas respectfully, while Y191H and A437S are associated with quinine resistance in the Americas. Recent studies have also reported the selection of pfmrp 856I alleles following the use of artemether-lumefantrine for the treatment of malaria [26]. The pfmrp 1466 K has been reported in sulfadoxine-pyrimethamine recrudescence treatment outcome [26].
The validation of the contribution of pfmrp to quinine and CQ resistance was reported by [27] after showing that knock out of PfMRP in CQ-resistant strain W2 rendered the parasite to be susceptible to CQ and quinine. Parasite with disrupted PfMRP also showed reduced IC50 values for primaquine, piperaquine, and artemisinin. The reduced IC50 for these drugs was modest, showing a reduced IC50 ranging from 38–57%. These may suggest that pfmrp might act as a secondary determinant in the modulation of parasite resistance to these antimalarial drugs [28].
2.4 P. falciparum Na+/H + exchanger 1 (Pfnhe-1)
The P. falciparum Na+/H+ exchanger 1 (Pfnhe-1) gene is a putative Na+/H+ exchanger found on chromosome 13 in the parasite genome. Some polymorphisms in the pfnhe-1 are involved in resistance to some antimalarial drugs whiles other polymorphisms result in increased susceptibility to other antimalarial drugs [3]. Parasites with the D-and N-rich polymorphism (microsatellite ms4760–1) have been reported to be resistant to quinine in clinical isolates from Asia, Southeast Asia, and Central and South America [3]. Resistance to quinine by this locus is ambiguous, with some scientists reporting increased quinine IC50 values in one study [29], and decreased quinine IC50 values in another study [30].
The destruction of pfnhe-1 in CQ and quinine resistant parasite strains 1BB5 and 3BA6 lead to an approximately 30% decrease in quinine mean IC50 values, but the knockdown of pfnhe-1 in CQ-sensitive GC03 strain did not lead to the reduction in quinine mean IC50 values [31]. These results suggest that pfnhe-1 contributes to quinine resistance in a strain-specific manner, and also other parasite genetic background factors are required for quinine resistance in parasites [28].
2.5 Plasmepsin II &III (pfmp2 and pfmp3)
The plasmepsins are aspartic proteases in P. falciparum that are involved in the degradation of hemoglobin. They are approximately 38-kDa in weight. The pfmp2 and pfmp3cleave hemoglobin in the parasite’s digestive vacuole [32]. Piperaquine, an aminoquinoline drug targets the pfmp2 and pfmp3 to inhibit them as its mode of action. An increase in pfmp2 and pfmp3 copy numbers have been associated with piperaquine resistance [33].
3. Molecular markers for resistance to antifolates
The antifolates used in malaria treatment are pyrimethamine, sulfadoxine, and proguanil. The proguanil is a cycloguanil metabolite that functions by interfering with folate metabolism [34]. The mode of action of pyrimethamine and cycloguanil is by inhibiting the dihydrofolate reductase (DHFR) enzyme, whiles sulfadoxine acts by inhibiting the dihydropteroate synthase (DHPS) enzyme, all involved in the folate metabolism pathway [34]. The sulfadoxine–pyrimethamine is used in a combination therapy to treat CQ-resistant parasites mostly in pregnant women in most malaria-endemic countries in Africa [34, 35].
Mutations in the DHFR are associated with resistance to pyrimethamine and cycloguanil, while mutations in DHPS are associated with sulfadoxine [36]. The pfdhfr S108N, N51I, C59R, and I164L are associated with pyrimethamine resistance, while pfdhfr A16V/S108T confers greater resistance to cycloguanil compared to pyrimethamine [37]. The quadruple mutant (S108N/N51I/C59R/I164L combination), which is mostly found in Asia but rare in Africa confers high levels of resistance to sulfadoxine–pyrimethamine [38]. The pfdhps S436A/F, A437G, K540E, A581G, and A613S/T mutations have been associated with resistance to sulfadoxine, with the pfdhps A437G mutation observed either alone or in combination with other mutations in field isolates [39]. The amplification of GTP-cyclohydrolase I, a gene involved in the upstream biosynthesis of folate is mostly seen with the pfdhfr I164L mutation in P. falciparum clinical isolates, and this is taught to compensate for the reduced efficiency of the pfdhfr I164L mutation in the parasite [40].
Artemisinin and its derivatives are the current in-use antimalarial drug in most malaria-endemic countries. Clinical resistance to artemisinin and its derivatives has not yet been defined, but what has been reported is delayed parasite clearance in clinical isolates from Cambodia. The emergence of delayed parasite clearance to artemisinin and its derivatives calls for concerns as it may emerge into full resistance [41]. This makes it important to identify molecular markers of resistance to artemisinin and its derivatives. A molecular marker that has been suggested to cause partial resistance to artemisinin and its derivatives is the ATP-consuming calcium-dependent P. falciparum SERCA ortholog, Pfatp6. The Pfatp6 L263E mutation has been associated with increased artemisinin and dihydroartemisinin IC50 values in D10 parasite strains. Parasite clinical isolates from France with the pfatp6 S769N mutation have been reported to have high IC50 values to artemether [42]. Another gene that has been associated with artemisinin and its derivatives is the Kelch 13 gene. The kelch 13 encodes 726 amino acids and located on chromosome 13 [43]. The kelch family of proteins has diverse functions, including organizing and interacting with other proteins. Mutations in the Kelch 13 gene that have been associated with artemisinin resistance include Y493H, R539T, I543T, F446L, P574L, and C580Y [43, 44].
Atovaquone has been in use since the 1980s when it was first developed for the treatment of malaria. Despite its high efficacy in the past, it is faced with a high level of recrudescence of approximately 30% when used as a monotherapy [45, 46]. Currently, atovaquone is used in combination with proguanil as a prophylaxis or treatment of malaria [47].
Atovaquone acts by inhibiting the electron transport in the mitochondria by interacting with the cytochrome b1 complex [48]. This makes the cytochrome b gene a molecular marker for the monitoring of atovaquone resistance (Table 1) [49]. The cytochrome b Y268S/C/N mutations have been associated with resistance to atovaquone. These mutations have been validated to cause resistance to atovaquone, in a study that introduces the mutation Y302C in the bacterial cytochrome b (this mutation corresponds to the Y268C in the P. falciparum) rendered the bacterial cytochrome bc1 less sensitive to atovaquone [50].
6. Molecular markers for drug resistance in P. vivax
The study of antimalarial drug resistance in P. vivax is hindered by the lack of in vitro culture techniques for the culturing of the parasite. This has made knowledge about the genetic basis of resistance in P. vivax limited. Insights about the genetic basis of antimalarial drugs in P. vivax have been gained by comparing it with P. falciparum.
Orthologs of pfcrt and pfmdr1 which are pvcrt-o and pvmdr1 respectively in P. vivax have been reported. P. vivax isolates with the pvmdr1 Y976F mutation are associated with higher CQ IC50 values. Studies show that the pvmdr1 Y976F mutation has reached near fixation in parasite isolates from Papua New Guinea, Indonesia [62], and Brazil [63], but CQ is still highly efficacious in these countries. These provide weak evidence for using pvmdr1 Y976F mutation as a CQ molecular marker of resistance in P. vivax, hence, CQ resistance in P. vivax may have a different genetic basis. Increased pvndr1 copy numbers have been recorded in P. vivax in regions Thailand where mefloquine is used extensively, but not in regions where mefloquine is less used [62, 64].
Mutations in dhfr and dhps in P. vivax have been associated with decreased susceptibility to sulfadoxine-pyrimethamine [65]. Studies by [65] have identified more than 20 alleles in the dhfr and dhps genes in P. vivax. An example of such a mutation is the PvDHFR S58R/S117N which are homologous to PfDHFR C59R/S108N mutations. The PvDHFR S117N has been reported to prevent binding pyrimethamine [66] just like the PfDHFR S108N [67].
The notable mutations in pfcrt 72–76 are associated with certain geographical locations. Other mutations outside these positions have no clear geographical association [68]. This makes it possible to identify or predict the evolution and geographical spread of chloroquine resistance-associated with mutations in pfcrt codons 72–76 by genotyping for these codons and the haplotype flanking this locus by microsatellite [68].
7.1 Route 1: southeast Asia to Africa
One of the most important routes, if not the most important for the spread of CQ-resistant parasite strains is the Southeast Asia to Africa route (Figure 1a). The CVIET (mutations in pfcrt from codons 72 to 76) lineage are responsible for the spread of CQ-resistance along this route. In the late 1950s, P. falciparum resistance to chloroquine was first identified in the Thai-Cambodian border. The spread of CQ-resistant parasites from Southeast Asia to Africa is considered to originate from the Thai-Cambodia border. The CQ-resistant parasites spread to Thailand in 1959 [68], and in Malaysia, Vietnam, and Cambodia in 1962 [68]. By the mid-1970s, CQ- resistance had been recorded in all Southeast Asia [68]. The SVMNT haplotype, which is mostly confined to the Pacific and South America has been reported in India and Laos [69, 70]. The CVIDT haplotype has also been reported [70, 71]. It remains a mystery whether these minor haplotypes found in Southeast Asia are due to new indigenous mutations or from other areas [68].
Figure 1.
Origins and geographical spread of CQ resistance. (A) Three different pfcrt mutants; the CVIET type, SVMNT type, and CVMNT type. Migration of the CVIET type from Southeast Asia to Africa is the most notable cause of CQ resistance in Africa. Capital letters are abbreviations of amino acids at positions 72–76 in pfcrt. Red-colored letters represent mutations. (B) Four different pfcrt mutants; CVMET type, SVMNT type, CVMNT type, s-SVNMT type originate from South America whiles CVIET type is imported from Southeast Asia. The v-S(agt)VMNT type has different bases at position 72 from the S(tct)VMNT type originated from Venezuela. Abbreviations are the same as in (A). Adapted from [68].
The first CQ-resistance was seen in Kenya in 1978 [68]. In the early 1980s, the CQ-resistance parasites spread to Comoro Island [68], Madagascar [68], Uganda [72], Zambia, and Malawi [68]. By the mid-1980s, CQ-resistant parasites had spread to Angola, Namibia [68]; and the western part of Africa, Nigeria, Benin, Togo, Ghana, Senegal, and Gambia [68]. The CVIET haplotype accounts for most of the CQ resistance in Africa [73]. The SVMNT haplotype has also been reported in Tanzania (in 19% of the field isolates) [74], whiles the SVIET haplotype is mostly confined to West Papua has been recorded in the Democratic Republic of Congo [75]. It remains unknown whether these haplotypes migrated from non-African regions or evolved indigenously [76].
7.2 Route 2: pacific regions
Chloroquine resistance was reported in the Pacific regions in the year 1959–1961 in West Papua, shortly after mass distribution of CQ [68]. The halting of the mass drug administration saw a reduction in the level of CQ-resistant but reemerged 10 years later [68]. The spread of resistance to other countries in the Pacific region like Papua New Guinea in 1976, the Solomon Islands in 1980, and Vanuatu in 1980 [68]. In the early 1980s, resistance was found in Sumatra and Java in Indonesia [77]. The common haplotype in the Pacific region is the SVMNT haplotype. In West Lombok in Indonesia, the CVIET haplotype is found in 10% of the P. falciparum clinical isolates [78]. The CVMNT has been recorded in indigenous P. falciparum lineage in the Philippines [79].
7.3 Route 3: south America
Chloroquine resistance was recorded in the 1960s in Columbia and Venezuela in South America [68]. Chloroquine-resistant parasites later spread to malaria-endemic regions in Brazil, Guyana in 1969, Suriname in 1972, Ecuador in 1976, Peru in 1980, and Bolivia in 1980 [68]. Two different CQ-resistant haplotypes are recorded in South America, which are the SVMNT and CVMET haplotypes with SVMNT haplotype being the most widely spread haplotype (Figure 1b) [1, 73]. This suggests that the SVMNT haplotype, originally found in Venezuela is responsible for the emergence of CQ-resistant isolates in South America [73, 80]. Recently, two other haplotypes; CVIET and CVMNT have been reported in Brazil and Peru respectively [81]. The CVIET haplotype might have been imported in South America from Southeast Asia or Africa [68].
7.4 Recovery of CQ resistance
The high level of CQ resistance in Malawi resulted in the ban of CQ for malaria treatment in Malawi in 1993. Just after 5 to 7 years after the CQ withdrawal, CQ sensitivity was observed [82, 83]. A decrease in the pfcrt K67T, which was 17% in 1998 and 2% in 2000 was observed [82]. Recovery of CQ resistance has been attributed to the expansion of wild-type pfcrt allele rather than a back mutation in the pfcrt allele [84]. This trend has also been recorded in Gabon, Vietnam [68], and China [85]. The rapid decrease in the CQ-resistance parasite population has been attributed to fitness costs incurred by the parasite as a result of the drug resistance [68].
7.5 Origins and spread of sulfadoxine-pyrimethamine resistance
Resistance to pyrimethamine was observed in the 1950s after it was used in mass drug administration and/or prophylaxis for malaria in most malaria-endemic regions [68]. Resistance to pyrimethamine led to it been used mostly as a first-line treatment option in sulfadoxine-pyrimethamine combination therapy in Thailand in the late 1960s, and most malaria-endemic countries in Southeast Asia, and South America in the 1970s and later in Africa [86].
7.6 Route 1: southeast Asia to Africa
P. falciparum resistance to SP was first reported in the 1960s at the Thai-Cambodia. Mutations in pfdhfr at codons 50,51,59,108, and 164 are CNRNI → CIRNI or CNRNL→CIRNL. These mutations have spread to other countries in Southeast Africa due to sulfadoxine-pyrimethamine pressure (Figure 2A) [87]. The pfdhfr quartet CIRNL mutant is dominant in Thailand [58], while the CIRNI mutant is found predominantly in Cambodia and Vietnam. The CNRNL mutant is found dominantly in Myanmar [87], while the CNRNI is found in Laos [88, 89]. Three additional genotypes, which are CNCNI, CICNI, and CICNL are also found in Southeast Asia at a very low prevalence of 5% [87]. The pfdhfr CIRNI mutant is predominant in many Africa countries such as South Africa, Benin, Cameroon, The Comoros, Congo, Gabon, Ghana, Guinea, Ivory Coast, Mali, Senegal, and Uganda (Figure 2A) [90]. This mutant is taught to have migrated to Africa from Asia [90]. It remains unknown when parasites resistant to pyrimethamine migrated to Africa, although some studies indicate the Asian origin triple mutant arrived in Kenya in 1987 [91].
Figure 2.
Origins and spread of pyrimethamine resistance. (A) A resistant lineage having a double mutation (CNRNI), from the Thai-Cambodia border, evolved into triple (CIRNI and CNRNL) and quartet (CIRNL) types and spread to other regions in Asia and Africa. Three indigenous lineages of the dhfr triple mutant evolved in Africa. In the Pacific region, two resistant lineages having the CNRNI type have been reported: An indigenous lineage and the lineage that migrated from Southeast Asia. Capital letters are abbreviations of amino acids at positions 50, 51, 59, 108, and 164 in dhfr. Red-colored letters represent mutations. (B) Two distinct lineages of pyrimethamine resistance have been detected in South America in Venezuela and Peru. The two triple mutants (RICNI and CICNL) lineages sequentially evolved from different lineages of the CICNI type of dhfr double mutant. Abbreviations are the same as in (A). Adapted from [68].
7.7 Route 2: pacific region
The pfdhfr CNRNI double mutant is predominant in malaria-endemic regions in the Pacific. The CNRNI has been reported to have two lineages, one which is indigenous and the other from Southeast Asia [92]. Resistance to pyrimethamine was observed in the early 1960s, after its introduction in a mass drug administration [68].
7.8 Route 3: south America
Resistance to pyrimethamine was first recorded in South America in the 1950s shortly after its introduction in Venezuela [68]. In vitro resistance to pyrimethamine was confirmed in Brazil in the mid 1960s [93] and Columbia in 1981 [68]. Since then, sulfadoxine-pyrimethamine-resistant parasites have spread to other countries in South America [94]. Parasites with pfdhfr evolved indigenously in South America. Two distinct pfdhfr lineages resistant to pyrimethamine have been confirmed in South America. The pfdhfr RICNI triple mutant has been confirmed in Venezuela [95], Bolivia [96], and Brazil [97]. The pfdhfr RICNI triple mutant is taught to have evolved from the CICNI double mutant. The second lineage, the CICNL triple mutant is found in Peru and Bolivia. The CICNL triple mutant has been suggested to evolve from the CICNI double mutant [96, 98].
References
1.Fidock, D. A., Nomura, T., Talley, A. K., Cooper, R. A., Dzekunov, S. M., Ferdig, M. T., Ursos, L. M. B., Sidhu, A. bir S., Naude´, B., Deitsch, K. W., Su, X., Wootton, J. C., Roepe, P. D., Wellems, and T. E., Wootton, J. C., Su, X., Naudé, B., Fidock, D. A., bir Singh Sidhu, A., … Nomura, T. (2000). Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Molecular Cell, 6(4), 861-871. https://doi.org/10.1016/s1097-2765(05)00077-8
2.Martin, R. E., & Kirk, K. (2004). The malaria parasite’s chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily. Molecular Biology and Evolution, 21(10), 1938-1949. https://doi.org/10.1093/molbev/msh205
3.Ferdig, M. T., Cooper, R. A., Mu, J., Deng, B., Joy, D. A., Su, X. Z., & Wellems, T. E. (2004). Dissecting the loci of low-level quinine resistance in malaria parasites. Molecular Microbiology, 52(4), 985-997. https://doi.org/10.1111/j.1365-2958.2004.04035.x
4.Mu, J., Myers, R. A., Jiang, H., Liu, S., Ricklefs, S., Waisberg, M., Chotivanich, K., Wilairatana, P., Krudsood, S., White, N. J., Udomsangpetch, R., Cui, L., Ho, M., Ou, F., Li, H., Song, J., Li, G., Wang, X., Seila, S., … Su, X. Z. (2010). Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs. Nature Genetics, 42(3), 268-271. https://doi.org/10.1038/ng.528
5.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., & Fidock, D. A. (2005). A critical role for PfCRT K76T in plasmodium falciparum verapamil-reversible chloroquine resistance. EMBO Journal, 24(13), 2294-2305. https://doi.org/10.1038/sj.emboj.7600681
6.Valderramos, S. G., & Fidock, D. A. (2006). Transporters involved in resistance to antimalarial drugs. Trends in Pharmacological Sciences, 27(11), 594-601. https://doi.org/10.1016/j.tips.2006.09.005
7.Bray, P. G., Martin, R. E., Tilley, L., Ward, S. A., Kirk, K., & Fidock, D. A. (2005). Defining the role of PfCRT in plasmodium falciparum chloroquine resistance. Molecular Microbiology, 56(2), 323-333. https://doi.org/10.1111/j.1365-2958.2005.04556.x
8.Singh Sidhu, A. B., Verdier-Pinard, D., & Fidock, D. A. (2002). Chloroquine resistance in plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science, 298(5591), 210-213. https://doi.org/10.1126/science.1074045
9.Holmgren, G., Gil, J. P., Ferreira, P. M., Veiga, M. I., Obonyo, C. O., & Björkman, A. (2006). Amodiaquine resistant plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y. Infection, Genetics and Evolution, 6(4), 309-314. https://doi.org/10.1016/j.meegid.2005.09.001
10.Sá, J. M., Twu, O., Hayton, K., Reyes, S., Fay, M. P., Ringwald, P., & Wellems, T. E. (2009). Geographic patterns of plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine . Proceedings of the National Academy of Sciences, 106(45), 18883-18889. https://doi.org/10.1073/pnas.0911317106
11.Sisowath, C., Ferreira, P. E., Bustamante, L. Y., Dahlström, S., Mårtensson, A., Björkman, A., Krishna, S., & Gil, J. P. (2007). The role of pfmdr1 in plasmodium falciparum tolerance to artemether-lumefantrine in Africa. Tropical Medicine and International Health, 12(6), 736-742. https://doi.org/10.1111/j.1365-3156.2007.01843.x
12.Cooper, R. A. (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. Molecular Pharmacology, 61(1), 35-42. https://doi.org/10.1124/mol.61.1.35
13.Wilson, C. M., Volkman, S. K., Thaithong, S., Martin, R. K., Kyle, D. E., Milhous, W. K., & Wirth, D. F. (1993). Amplification of pfmdr1 associated with mefloquine and halofantrine resistance in plasmodium falciparum from Thailand. Molecular and Biochemical Parasitology, 57(1), 151-160. https://doi.org/10.1016/0166-6851(93)90252-S
14.Nelson, A. L., Purfield, A., McDaniel, P., Uthaimongkol, N., Buathong, N., Sriwichai, S., Miller, R. S., Wongsrichanalai, C., & Meshnick, S. R. (2005). pfmdr1 genotyping and in vivo mefloquine resistance on the Thai-Myanmar border. American Journal of Tropical Medicine and Hygiene, 72(5), 586-592. https://doi.org/10.4269/ajtmh.2005.72.586
15.Alker, A. P., Lim, P., Sem, R., Shah, N. K., Yi, P., Bouth, D. M., Tsuyuoka, R., Maguire, J. D., Fandeur, T., Ariey, F., Wongsrichanalai, C., & Meshnick, S. R. (2007). PFMDR1 and in vivo resistance to artesunate-mefloquine in falciparum malaria on the Cambodian-Thai border. American Journal of Tropical Medicine and Hygiene, 76(4), 641-647. https://doi.org/10.4269/ajtmh.2007.76.641
16.Sidhu, A. B. S., Uhlemann, A., Valderramos, S. G., Valderramos, J., Krishna, S., & Fidock, D. A. (2006). Decreasing pfmdr1 copy number in plasmodium falciparum malaria heightens susceptibility to Mefloquine, Lumefantrine, Halofantrine, quinine, and artemisinin . The Journal of Infectious Diseases, 194(4), 528-535. https://doi.org/10.1086/507115
17.Volkman, S. K., Cowman, A. F., & Wirth, D. F. (1995). Functional complementation of the ste6 gene of Saccharomyces cerevisiae with the pfmdr1 gene of plasmodium falciparum. Proceedings of the National Academy of Sciences of the United States of America, 92(19), 8921-8925. https://doi.org/10.1073/pnas.92.19.8921
18.Picot, S., Olliaro, P., De Monbrison, F., Bienvenu, A. L., Price, R. N., & Ringwald, P. (2009). A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria. Malaria Journal, 8(1), 1-15. https://doi.org/10.1186/1475-2875-8-89
19.Holmgren, G., Hamrin, J., Svärd, J., Mårtensson, A., Gil, J. P., & Björkman, A. (2007). Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa. Infection, Genetics and Evolution, 7(5), 562-569. https://doi.org/10.1016/j.meegid.2007.03.005
20.Echeverry, D. F., Holmgren, G., Murillo, C., Higuita, J. C., Björkman, A., Gil, J. P., & Osorio, L. (2007). Short report: Polymorphisms in the pfcrt and pfmdr1 genes of plasmodium falciparum and in vitro susceptibility to amodiaquine and desethylamodiaquine. American Journal of Tropical Medicine and Hygiene, 77(6), 1034-1038. https://doi.org/10.4269/ajtmh.2007.77.1034
21.Dokomajilar, C., Nsobya, S. L., Greenhouse, B., Rosenthal, P. J., & Dorsey, G. (2006). Selection of plasmodium falciparum pfmdr1 alleles following therapy with artemether-lumefantrine in an area of Uganda where malaria is highly endemic. Antimicrobial Agents and Chemotherapy, 50(5), 1893-1895. https://doi.org/10.1128/AAC.50.5.1893-1895.2006
22.Sisowath, C., Petersen, I., Veiga, M. I., Mårtensson, A., Premji, Z., Björkman, A., Fidock, D. A., & Gil, J. P. (2009). In vivo selection of plasmodium falciparum parasites carrying the chloroquine-susceptible pfcrt K76 allele after treatment with Artemether-Lumefantrine in Africa . Journal of Infectious Diseases, 199(5), 750-757. https://doi.org/10.1086/596738
23.Anderson, T. J. C., Nair, S., Qin, H., Singlam, S., Brockman, A., Paiphun, L., & Nosten, F. (2005). Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance? Antimicrobial Agents and Chemotherapy, 49(6), 2180-2188. https://doi.org/10.1128/AAC.49.6.2180-2188.2005
24.Reed, M. B., Saliba, K. J., Caruana, S. R., Kirk, K., & Cowman, A. F. (2000). Pgh1 modulates sensitivity and resistance to multiple antimalarials in plasmodium falciparum. Nature, 403(6772), 906-909. https://doi.org/10.1038/35002615
25.Mu, J., Ferdig, M. T., Feng, X., Joy, D. A., Duan, J., Furuya, T., Subramanian, G., Aravind, L., Cooper, R. A., Wootton, J. C., Xiong, M., & Su, X. Z. (2003). Multiple transporters associated with malaria parasite responses to chloroquine and quinine. Molecular Microbiology, 49(4), 977-989. https://doi.org/10.1046/j.1365-2958.2003.03627.x
26.Dahlström, S., Veiga, M. I., Mårtensson, A., Björkman, A., & Gil, J. P. (2009). Polymorphism in Pfmrp1 (plasmodium falciparum multidrug resistance protein 1) amino acid 1466 associated with resistance to sulfadoxine-pyrimethamine treatment. Antimicrobial Agents and Chemotherapy, 53(6), 2553-2556. https://doi.org/10.1128/AAC.00091-09
27.Raj, D. K., Mu, J., Jiang, H., Kabat, J., Singh, S., Sullivan, M., Fay, M. P., McCutchan, T. F., & Su, X. Z. (2009). Disruption of a plasmodium falciparum multidrug resistance-associated protein (PfMRP) alters its fitness and transport of antimalarial drugs and glutathione. Journal of Biological Chemistry, 284(12), 7687-7696. https://doi.org/10.1074/jbc.M806944200
28.Ecker, A., Lehane, A. M., Clain, J., & Fidock, D. A. (2012). PfCRT and its role in antimalarial drug resistance Andrea. 4(Novenber 2012), 504-514. https://doi.org/10.1016/j.pt.2012.08.002.PfCRT
29.Andriantsoanirina, V., Ménard, D., Rabearimanana, S., Hubert, V., Bouchier, C., Tichit, M., Le Bras, J., & Durand, R. (2010). Association of microsatellite variations of plasmodium falciparum Na+/H+ exchanger (Pfnhe-1) gene with reduced in vitro susceptibility to quinine: Lack of confirmation in clinical isolates from Africa. American Journal of Tropical Medicine and Hygiene, 82(5), 782-787. https://doi.org/10.4269/ajtmh.2010.09-0327
30.Henry, M., Briolant, S., Zettor, A., Pelleau, S., Baragatti, M., Baret, E., Mosnier, J., Amalvict, R., Fusai, T., Rogier, C., & Pradines, B. (2009). Plasmodium falciparum Na+/H+ exchanger 1 transporter is involved in reduced susceptibility to quinine. Antimicrobial Agents and Chemotherapy, 53(5), 1926-1930. https://doi.org/10.1128/AAC.01243-08
31.Nkrumah, L. J., Riegelhaupt, P. M., Moura, P., Johnson, D. J., Patel, J., Hayton, K., Ferdig, M. T., Wellems, T. E., Akabas, M. H., & Fidock, D. A. (2009). Probing the multifactorial basis of plasmodium falciparum quinine resistance: Evidence for a strain-specific contribution of the sodium-proton exchanger PfNHE. Molecular and Biochemical Parasitology, 165(2), 122-131. https://doi.org/10.1016/j.molbiopara.2009.01.011
32.Banerjee, R., Liu, J., Beatty, W., Pelosof, L., Klemba, M., & Goldberg, D. E. (2002). Four plasmepsins are active in the plasmodium falciparum food vacuole, including a protease with an active-site histidine. Proceedings of the National Academy of Sciences, 99(2), 990-995. https://doi.org/10.1073/pnas.022630099
33.Bopp, S., Magistrado, P., Wong, W., Schaffner, S. F., Mukherjee, A., Lim, P., Dhorda, M., Amaratunga, C., Woodrow, C. J., Ashley, E. A., White, N. J., Dondorp, A. M., Fairhurst, R. M., Ariey, F., Menard, D., Wirth, D. F., & Volkman, S. K. (2018). Plasmepsin II-III copy number accounts for bimodal piperaquine resistance among Cambodian plasmodium falciparum. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-04104-z
34.Wongsrichanalai, C., Pickard, A. L., Wernsdorfer, W. H., & Meshnick, S. R. (2002). Reviews Epidemiology of drug-resistant malaria. 2, 209-218
35.Harrington, W. E., Mutabingwa, T. K., Muehlenbachs, A., Sorensen, B., Bolla, M. C., Fried, M., & Duffy, P. E. (2009). Competitive facilitation of drug-resistant plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment. Proceedings of the National Academy of Sciences of the United States of America, 106(22), 9027-9032. https://doi.org/10.1073/pnas.0901415106
36.Peterson, D. S., Walliker, D., & Wellems, T. E. (1988). Evidence that a point mutation in dihydrofolate reductase- thymidylate synthase confers resistance to pyrimethamine in falciparum malaria (Plasmodiumfakiparum/drug resistance/folic acid antagonists/genetic linkage analysis/polymerase chain reaction). Genetics Communicated by George H. Hitchings, 85(December), 9114-9118. http://www.pnas.org/content/85/23/9114.full.pdf
37.Foote, S. J., Galatis, D., & Cowman, A. F. (1990). Amino acids in the dihydrofolate reductase-thymidylate synthase gene of plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proceedings of the National Academy of Sciences of the United States of America, 87(8), 3014-3017. https://doi.org/10.1073/pnas.87.8.3014
38.Kiara, S. M., Okombo, J., Masseno, V., Mwai, L., Ochola, I., Borrmann, S., & Nzila, A. (2009). In vitro activity of antifolate and polymorphism in dihydrofolate reductase of plasmodium falciparum isolates from the Kenyan coast: Emergence of parasites with Ile-164-Leu mutation. Antimicrobial Agents and Chemotherapy, 53(9), 3793-3798. https://doi.org/10.1128/AAC.00308-09
39.Price, R. N., Dorsey, G., Ashley, E. A., Barnes, K. I., Baird, J. K., D’Alessandro, U., Guerin, P. J., Laufer, M. K., Naidoo, I., Nosten, F., Olliaro, P., Plowe, C. V., Ringwald, P., Sibley, C. H., Stepniewska, K., & White, N. J. (2007). World antimalarial resistance network I: Clinical efficacy of antimalarial drugs. Malaria Journal, 6, 1-9. https://doi.org/10.1186/1475-2875-6-119
40.Nair, S., Miller, B., Barends, M., Jaidee, A., Patel, J., Mayxay, M., Newton, P., Nosten, F., Ferdig, M. T., & Anderson, T. J. C. (2008). Adaptive copy number evolution in malaria parasites. PLoS Genetics, 4(10). https://doi.org/10.1371/journal.pgen.1000243
41.Noedl, H., Se, Y., Schaecher, K., Smith, B. L., Socheat, D., & Fukuda, M. M. (2008). Evidence of artemisinin-resistant malaria in Western Cambodia. New England Journal of Medicine, 359(24), 2619-2620. https://doi.org/10.1056/NEJMc0805011
42.Krishna, S., Pulcini, S., Fatih, F., & Staines, H. (2010). Artemisinins and the biological basis for the PfATP6/SERCA hypothesis. Trends in Parasitology, 26(11), 517-523. https://doi.org/10.1016/j.pt.2010.06.014
43.Ariey, F., Witkowski, B., Amaratunga, C., Beghain, J., Langlois, A. C., Khim, N., Kim, S., Duru, V., Bouchier, C., Ma, L., Lim, P., Leang, R., Duong, S., Sreng, S., Suon, S., Chuor, C. M., Bout, D. M., Ménard, S., Rogers, W. O., … Ménard, D. (2014). A molecular marker of artemisinin-resistant plasmodium falciparum malaria. Nature, 505(7481), 50-55. https://doi.org/10.1038/nature12876
44.Ashley, E. A., Dhorda, M., Fairhurst, R. M., Amaratunga, C., Lim, P., Suon, S., Sreng, S., Anderson, J. M., Mao, S., Sam, B., Sopha, C., Chuor, C. M., Nguon, C., Sovannaroth, S., Pukrittayakamee, S., Jittamala, P., Chotivanich, K., Chutasmit, K., Suchatsoonthorn, C., … White, N. J. (2014). Spread of artemisinin resistance in plasmodium falciparum malaria. New England Journal of Medicine, 371(5), 411-423. https://doi.org/10.1056/NEJMoa1314981
45.Looareesuwan, S., Chulay, J. D., Canfield, C. J., Hutchinson, D. B. A., De Alencar, F., Anabwani, G., Attanath, P., Bienzle, U., Bouchaud, O., Bustos, D., Campos, P., Cerutti, C., Charoenlarp, P., Chiodini, P., Chongsuphajaisiddihi, T., Clendenes, M., Conlon, C., Coulaud, J. P., Danis, M., … Wilairatana, P. (1999). Malarone(TM) (atovaquone and proguanil hydrochloride): A review of its clinical development for treatment of malaria. American Journal of Tropical Medicine and Hygiene, 60(4), 533-541. https://doi.org/10.4269/ajtmh.1999.60.533
46.Chiodini, P. L., Conlon, C. P., Hutchinson, D. B. A., Farquhar, J. A., Hall, A. P., Peto, T. E. A., Birley, H., & Warrell, D. A. (1995). Evaluation of atovaquone in the treatment of patients with uncomplicated plasmodium falciparum malaria. Journal of Antimicrobial Chemotherapy, 36(6), 1073-1078. https://doi.org/10.1093/jac/36.6.1073
47.Nakato, H., Vivancos, R., & Hunter, P. R. (2007). A systematic review and meta-analysis of the effectiveness and safety of atovaquone - Proguanil (Malarone) for chemoprophylaxis against malaria. Journal of Antimicrobial Chemotherapy, 60(5), 929-936. https://doi.org/10.1093/jac/dkm337
48.Fry, M., & Pudney, M. (1992). Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4′-chlorophenyl) cyclohexyl]-3- hydroxy-1,4-naphthoquinone (566C80). Biochemical Pharmacology, 43(7), 1545-1553. https://doi.org/10.1016/0006-2952(92)90213-3
49.Srivastava, I. K., Morrlsey, J. M., Darrouzet, E., Daldal, F., & Vaidya, A. B. (1999). Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites. Molecular Microbiology, 33(4), 704-711. https://doi.org/10.1046/j.1365-2958.1999.01515.x
50.Mather, M. W., Darrouzet, E., Valkova-Valchanova, M., Cooley, J. W., McIntosht, M. T., Daldal, F., & Vaidya, A. B. (2005). Uncovering the molecular mode of action of the antimalarial drug atovaquone using a bacterial system. Journal of Biological Chemistry, 280(29), 27458-27465. https://doi.org/10.1074/jbc.M502319200
51.Sidhu, A. B. S., Valderramos, S. G., & Fidock, D. A. (2005). pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in plasmodium falciparum. Molecular Microbiology, 57(4), 913-926. https://doi.org/10.1111/j.1365-2958.2005.04729.x
52.Muhamad, P., Phompradit, P., Sornjai, W., Maensathian, T., Chaijaroenkul, W., Rueangweerayut, R., & Na-Bangchang, K. (2011). Polymorphisms of molecular markers of antimalarial drug resistance and relationship with artesunate-mefloquine combination therapy in patients with uncomplicated plasmodium falciparum malaria in Thailand. American Journal of Tropical Medicine and Hygiene, 85(3), 568-572. https://doi.org/10.4269/ajtmh.2011.11-0194
53.Price, R. N., Uhlemann, A., Brockman, A., Mcgready, R., Ashley, E., Phaipun, L., Patel, R., Laing, K., Looareesuwan, S., White, N. J., Nosten, F., & Krishna, S. (2015). Europe PMC Funders Group Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. 364(9432), 438-447. https://doi.org/10.1016/S0140-6736(04)16767-6.Mefloquine
54.Mungthin, M., Khositnithikul, R., Sitthichot, N., Suwandittakul, N., Wattanaveeradej, V., Ward, S. A., & Na-Bangchang, K. (2010). Association between the pfmdr1 gene and in vitro artemether and lumefantrine sensitivity in thai isolates of plasmodium falciparum. American Journal of Tropical Medicine and Hygiene, 83(5), 1005-1009. https://doi.org/10.4269/ajtmh.2010.10-0339
55.DJIMDÉ, A. B., DOUMBO, O. K., CORTESE, J. F., KAYENTAO, K., DOUMBO, S., DIOURTÉ, Y., DICKO, A., SU, X.-Z., OMURA, A. N., FIDOCK, D. A., WELLEMS, T. E., & PLOWE, C. V. (2001). A molecular marker for chloroquine-resistant falciparum malaria. English Journal, 344(4), 257-263. http://www.ncbi.nlm.nih.gov/pubmed/11172152
56.Folarin, O. A., Bustamante, C., Gbotosho, G. O., Sowunmi, A., Zalis, M. G., Oduola, A. M. J., & Happi, C. T. (2011). In vitro amodiaquine resistance and its association with mutations in pfcrt and pfmdr1 genes of plasmodium falciparum isolates from Nigeria. Acta Tropica, 120(3), 224-230. https://doi.org/10.1016/j.actatropica.2011.08.013
57.Witkowski, B., Duru, V., Khim, N., Ross, L. S., Saintpierre, B., Beghain, J., Chy, S., Kim, S., Ke, S., Kloeung, N., Eam, R., Khean, C., Ken, M., Loch, K., Bouillon, A., Domergue, A., Ma, L., Bouchier, C., Leang, R., … Ménard, D. (2017). A surrogate marker of piperaquine-resistant plasmodium falciparum malaria: A phenotype–genotype association study. The Lancet Infectious Diseases, 17(2), 174-183. https://doi.org/10.1016/S1473-3099(16)30415-7
58.Rout, S., & Mahapatra, R. K. (2019). Plasmodium falciparum: Multidrug resistance. Chemical Biology and Drug Design, 93(5), 737-759. https://doi.org/10.1111/cbdd.13484
59.Pillai, D. R., Lau, R., Khairnar, K., Lepore, R., Via, A., Staines, H. M., & Krishna, S. (2012). Artemether resistance in vitro is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with plasmodium falciparum infections. Malaria Journal, 11, 1-9. https://doi.org/10.1186/1475-2875-11-131
60.Severini, C., & Menegon, M. (2015). Resistance to antimalarial drugs: An endless world war against plasmodium that we risk losing. Journal of Global Antimicrobial Resistance, 3(2), 58-63. https://doi.org/10.1016/j.jgar.2015.02.002
61.Olliaro, P. (2001). Mode of action and mechanisms of resistance for antimalarial drugs. Pharmacology and Therapeutics, 89(2), 207-219. https://doi.org/10.1016/S0163-7258(00)00115-7
62.Suwanarusk, R., Russell, B., Chavchich, M., Chalfein, F., Kenangalem, E., Kosaisavee, V., Prasetyorini, B., Piera, K. A., Barends, M., Brockman, A., Lek-Uthai, U., Anstey, N. M., Tjitra, E., Nosten, F., Cheng, Q., & Price, R. N. (2007). Chloroquine resistant plasmodium vivax: In vitro characterisation and association with molecular polymorphisms. PLoS ONE, 2(10), 1-9. https://doi.org/10.1371/journal.pone.0001089
63.Gama, B. E., de Oliveira, N. K. A., de Souza, J. M., Daniel-Ribeiro, C. T., & Ferreira-da-Cruz, M. de F. (2009). Characterisation of pvmdr1 and pvdhfr genes associated with chemoresistance in Brazilian plasmodium vivax isolates. Memorias Do Instituto Oswaldo Cruz, 104(7), 1009-1011. https://doi.org/10.1590/S0074-02762009000700012
64.Imwong, M., Pukrittayakamee, S., Pongtavornpinyo, W., Nakeesathit, S., Nair, S., Newton, P., Nosten, F., Anderson, T. J. C., Dondorp, A., Day, N. P. J., & White, N. J. (2008). Gene amplification of the multidrug resistance 1 gene of plasmodium vivax isolates from Thailand, Laos, and Myanmar. Antimicrobial Agents and Chemotherapy, 52(7), 2657-2659. https://doi.org/10.1128/AAC.01459-07
65.Hawkins, V. N., Joshi, H., Rungsihirunrat, K., Na-Bangchang, K., & Sibley, C. H. (2007). Antifolates can have a role in the treatment of plasmodium vivax. Trends in Parasitology, 23(5), 213-222. https://doi.org/10.1016/j.pt.2007.03.002
66.Kongsaeree, P., Khongsuk, P., Leartsakulpanich, U., Chitnumsub, P., Tarnchompoo, B., Walkinshaw, M. D., & Yuthavong, Y. (2005). Crystal structure of dihydrofolate reductase from plasmodium vivax: Pyrimethamine displacement linked with mutation-induced resistance. Proceedings of the National Academy of Sciences of the United States of America, 102(37), 13046-13051. https://doi.org/10.1073/pnas.0501747102
67.Yuvaniyama, J., Chitnumsub, P., Kamchonwongpaisan, S., Vanichtanankul, J., Sirawaraporn, W., Taylor, P., Walkinshaw, M. D., & Yuthavong, Y. (2003). Insights into antifolate resistance from malarial DHFR-TS structures. Nature Structural Biology, 10(5), 357-365. https://doi.org/10.1038/nsb921
68.Mita, T., Tanabe, K., & Kita, K. (2009). Spread and evolution of plasmodium falciparum drug resistance. Parasitology International, 58(3), 201-209. https://doi.org/10.1016/j.parint.2009.04.004
69.Dittrich, S., Alifrangis, M., Stohrer, J. M., Thongpaseuth, V., Vanisaveth, V., Phetsouvanh, R., Phompida, S., Khalil, I. F., & Jelinek, T. (2005). Falciparum malaria in the north of Laos: The occurrence and implications of the plasmodium falciparum chloroquine resistance transporter (pfcrt) gene haplotype SVMNT. Tropical Medicine and International Health, 10(12), 1267-1270. https://doi.org/10.1111/j.1365-3156.2005.01514.x
70.Lim, P., Chy, S., Ariey, F., Incardona, S., Chim, P., Sem, R., Denis, M. B., Hewitt, S., Hoyer, S., Socheat, D., Merecreau-Puijalon, O., & Fandeur, T. (2003). Pfcrt polymorphism and chloroquine resistance in plasmodium falciparum strains isolated in Cambodia. Antimicrobial Agents and Chemotherapy, 47(1), 87-94. https://doi.org/10.1128/AAC.47.1.87-94.2003
71.Durrand, V., Berry, A., Sem, R., Glaziou, P., Beaudou, J., & Fandeur, T. (2004). Variations in the sequence and expression of the plasmodium falciparum chloroquine resistance transporter (Pfcrt) and their relationship to chloroquine resistance in vitro. Molecular and Biochemical Parasitology, 136(2), 273-285. https://doi.org/10.1016/j.molbiopara.2004.03.016
72.Onori, E. (1984). The problem of plasmodium falciparum drug resistance in Africa south of the Sahara. Bulletin of the World Health Organization, 62(SUPPL.), 55-62
73.Wootton, J. C., Feng, X., Ferdig, M. T., Cooper, R. A., Mu, J., Baruch, D. I., Magill, A. J., & Su, X. Z. (2002). Genetic diversity and chloroquine selective sweeps in plasmodium falciparum. Nature, 418(6895), 320-323. https://doi.org/10.1038/nature00813
74.Alifrangis, M., Dalgaard, M. B., Lusingu, J. P., Vestergaard, L. S., Staalsoe, T., Jensen, A. T. R., Enevold, A., Rønn, A. M., Khalil, I. F., Warhurst, D. C., Lemnge, M. M., Theander, T. G., & Bygbjerg, I. C. (2006). Occurrence of the southeast Asian/south American SVMNT haplotype of the chloroquine-resistance transporter gene in plasmodium falciparum in Tanzania. Journal of Infectious Diseases, 193(12), 1738-1741. https://doi.org/10.1086/504269
75.Severini, C., Menegon, M., Sannella, A. R., Paglia, M. G., Narciso, P., Matteelli, A., Gulletta, M., Caramello, P., Canta, F., Xayavong, M. V., Moura, I. N. S., Pieniazek, N. J., Taramelli, D., & Majori, G. (2006). Prevalence of pfcrt point mutations and level of chloroquine resistance in plasmodium falciparum isolates from Africa. Infection, Genetics and Evolution, 6(4), 262-268. https://doi.org/10.1016/j.meegid.2005.07.002
76.Zakeri, S., Afsharpad, M., Kazemzadeh, T., Mehdizadeh, K., Shabani, A., & Djadid, N. D. (2008). Association of pfcrt but not pfmdr1 alleles with chloroquine resistance in Iranian isolates of plasmodium falciparum. American Journal of Tropical Medicine and Hygiene, 78(4), 633-640. https://doi.org/10.4269/ajtmh.2008.78.633
77.Smrkovski, L. L., Hoffman, S. L., Purnomo, Hussein, R. P., Masbar, S., & Kurniawan, L. (1983). Chloroquine resistant plasmodium falciparum on the island of Flores, Indonesia. Transactions of the Royal Society of Tropical Medicine and Hygiene, 77(4), 459-462. https://doi.org/10.1016/0035-9203(83)90112-8
78.Mehlotra, R. K., Mattera, G., Bockarie, M. J., Maguire, J. D., Baird, J. K., Sharma, Y. D., Alifrangis, M., Dorsey, G., Rosenthal, P. J., Fryauff, D. J., Kazura, J. W., Stoneking, M., & Zimmerman, P. A. (2008). Discordant patterns of genetic variation at two chloroquine resistance loci in worldwide populations of the malaria parasite plasmodium falciparum. Antimicrobial Agents and Chemotherapy, 52(6), 2212-2222. https://doi.org/10.1128/AAC.00089-08
79.Chen, N., Wilson, D. W., Pasay, C., Bell, D., Martin, L. B., Kyle, D., & Cheng, Q. (2005). Origin and dissemination of chloroquine-resistant plasmodium falciparum with mutant pfcrt alleles in the Philippines. Antimicrobial Agents and Chemotherapy, 49(5), 2102-2105. https://doi.org/10.1128/AAC.49.5.2102-2105.2005
80.Cortese, J. F., Caraballo, A., Contreras, C. E., & Plowe, C. V. (2002). Origin and dissemination of plasmodium falciparum drug-resistance mutations in South America. Journal of Infectious Diseases, 186(7), 999-1006. https://doi.org/10.1086/342946
81.Vieira, P. P., Ferreira, M. U., Alecrim, M. D. G., Alecrim, W. D., Da Silva, L. H. P., Sihuincha, M. M., Joy, D. A., Mu, J., Su, X. Z., & Zalis, M. G. (2004). Pfcrt polymorphism and the spread of chloroquine resistance in plasmodium falciparum populations across the Amazon Basin. Journal of Infectious Diseases, 190(2), 417-424. https://doi.org/10.1086/422006
82.Mita, T., Kaneko, A., Lum, J. K., Bwijo, B., Takechi, M., Zungu, I. L., Tsukahara, T., Tanabe, K., Kobayakawa, T., & Björkman, A. (2003). Recovery of chloroquine sensitivity and low prevalence of the plasmodium falciparum chloroquine resistance transporter gene mutation K76T following the discontinuance of chloroquine use in Malawi. American Journal of Tropical Medicine and Hygiene, 68(4), 413-415. https://doi.org/10.4269/ajtmh.2003.68.413
83.Takechi, M., Matsuo, M., Ziba, C., Macheso, A., Butao, D., Zungu, I. L., Chakanika, I., & Bustos, M. D. G. (2001). Therapeutic efficacy of sulphadoxine/pyrimethamine and susceptibility in vitro of P. falciparum isolates to sulphadoxine-pyremethamine and other antimalarial drugs in Malawian children. Tropical Medicine and International Health, 6(6), 429-434. https://doi.org/10.1046/j.1365-3156.2001.00735.x
84.Mita, T., Kaneko, A., Lum, J. K., Zungu, I. L., Tsukahara, T., Eto, H., Kobayakawa, T., Björkman, A., & Tanabe, K. (2004). Expansion of wild type allele rather than back mutation in pfcrt explains the recent recovery of chloroquine sensitivity of plasmodium falciparum in Malawi. Molecular and Biochemical Parasitology, 135(1), 159-163. https://doi.org/10.1016/j.molbiopara.2004.01.011
85.Liu, D. Q., Liu, R. J., Ren, D. X., Gao, D. Q., Zhang, C. Y., Qiu, C. P., Cai, X. Z., Ling, C. F., Song, A. H., & Tang, X. (1995). Changes in the resistance of plasmodium falciparum to chloroquine in Hainan, China. Bulletin of the World Health Organization, 73(4), 483-486
86.Black, F., Bygbjerg, I., Effersoe, P., Gomme, G., Jepsen, S., & Axelgaard Jensen, G. (1981). Fansidar resistant falciparum malaria acquired in south east asia. Transactions of the Royal Society of Tropical Medicine and Hygiene, 75(5), 715-716. https://doi.org/10.1016/0035-9203(81)90160-7
87.Nair, S., Williams, J. T., Brockman, A., Paiphun, L., Mayxay, M., Newton, P. N., Guthmann, J. P., Smithuis, F. M., Hien, T. T., White, N. J., Nosten, F., & Anderson, T. J. C. (2003). A selective sweep driven by pyrimethamine treatment in southeast Asian malaria parasites. Molecular Biology and Evolution, 20(9), 1526-1536. https://doi.org/10.1093/molbev/msg162
88.Nash, D., Nair, S., Mayxay, M., Newton, P. N., Guthmann, J. P., Nosten, F., & Anderson, T. J. C. (2005). Selection strength and hitchhiking around two anti-malarial resistance genes. Proceedings of the Royal Society B: Biological Sciences, 272(1568), 1153-1161. https://doi.org/10.1098/rspb.2004.3026
89.Toma, H., Imada, Y., Vannachone, B., Miyagi, M., Kobayashi, J., Uechi, G., Pethuvang, R., Manivong, K., Phompida, S., Sato, Y., Station, M., Provincial, K., & Office, H. (2005). RESEARCH NOTE A MOLECULAR EPIDEMIOLOGIC STUDY OF POINT MUTATIONS FOR PYRIMETHAMINE-SULFADOXINE RESISTANCE OF 36(3), 1-3
90.Maïga, O., Djimdé, A. A., Hubert, V., Renard, E., Aubouy, A., Kironde, F., Nsimba, B., Koram, K., Doumbo, O. K., Le Bras, J., & Clain, J. (2007). A shared asian origin of the triple-mutant dhfr allele in plasmodium falciparum from sites across Africa. Journal of Infectious Diseases, 196(1), 165-172. https://doi.org/10.1086/518512
91.Certain, L. K., Briceño, M., Kiara, S. M., Nzila, A. M., Watkins, W. M., & Sibley, C. H. (2008). Characteristics of plasmodium falciparum dhfr haplotypes that confer pyrimethamine resistance, Kilifi, Kenya, 1987-2006. Journal of Infectious Diseases, 197(12), 1743-1751. https://doi.org/10.1086/588198
92.Mita, T., Tanabe, K., Takahashi, N., Tsukahara, T., Eto, H., Dysoley, L., Ohmae, H., Kita, K., Krudsood, S., Looareesuwan, S., Kaneko, A., Björkman, A., & Kobayakawa, T. (2007). Independent evolution of pyrimethamine resistance in plasmodium falciparum isolates in Melanesia. Antimicrobial Agents and Chemotherapy, 51(3), 1071-1077. https://doi.org/10.1128/AAC.01186-06
93.Walker, A. J., & Lopez-Antunano, F. J. (1968). Response to drugs of south american strains of plasmodium falciparum. Transactions of the Royal Society of Tropical Medicine and Hygiene, 62(5), 654-667. https://doi.org/10.1016/0035-9203(68)90116-8
94.Kremsner, P. G., Zotter, G. M., Feldmeier, H., Graninger, W., Kollaritsch, M., Wiedermann, G., Rocha, R. M., & Wernsdorfer, W. H. (1989). In vitro drug sensitivity of plasmodium falciparum in acre, Brazil. Bulletin of the World Health Organization, 67(3), 289-293
95.McCollum, A. M., Mueller, K., Villegas, L., Udhayakumar, V., & Escalante, A. A. (2007). Common origin and fixation of plasmodium falciparum dhfr and dhps mutations associated with sulfadoxine-pyrimethamine resistance in a low-transmission area in South America. Antimicrobial Agents and Chemotherapy, 51(6), 2085-2091. https://doi.org/10.1128/AAC.01228-06
96.Cortese, J. F., & Plowe, C. V. (1998). Antifolate resistance due to new and known plasmodium falciparum dihydrofolate reductase mutations expressed in yeast. Molecular and Biochemical Parasitology, 94(2), 205-214. https://doi.org/10.1016/S0166-6851(98)00075-9
97.Vasconcelos, K. F., Plowe, C. V., Fontes, C. J., Kyle, D., Wirth, D. F., Pereira Da Silva, L. H., & Zalis, M. G. (2000). Mutations in plasmodium falciparum Dihydrofolate reductase and Dihydropteroate synthase of isolates from the Amazon region of Brazil. Memorias Do Instituto Oswaldo Cruz, 95(5), 721-728. https://doi.org/10.1590/S0074-02762000000500020
98.Zhou, Z., Griffing, S. M., De Oliveira, A. M., McCollum, A. M., Quezada, W. M., Arrospide, N., Escalante, A. A., & Udhayakumar, V. (2008). Decline in sulfadoxine-pyrimethamine-resistant alleles after change in drug policy in the Amazon region of Peru. Antimicrobial Agents and Chemotherapy, 52(2), 739-741. https://doi.org/10.1128/AAC.00975-07
Written By
Peter Hodoameda
Submitted: 11 January 2021Reviewed: 12 May 2021Published: 08 July 2021
Open access peer-reviewed chapter
