Mechanisms of sulfadoxine pyrimethamine resistance and health implication in Plasmodium falciparum malaria: A mini review


Sulfadoxine pyrimethamine was adopted by most African countries based on the recommendation Roll Back Malaria. However, parasite resistant to the drug emerged quicker than Chloroquine resistant and it now becoming an alarming issue in Africa where the malaria burden is high. Although there are lot of studies on sulfadoxine pyrimethamine resistance (SPR), including the identification of the genes responsible for SPR, many question remained unanswered. In this mini review, recent advances of the mechanism of SPR and its impact on health in Africa is highlighted with emphasise on the role of mutation in SPR. It is no doubt that better understanding of SPR will eventually lead to more effective malaria control measures.

Keywords: Dihydrofolate reductase, dihydopteroate synthase, malaria, Plasmodium falciparum, sulfadoxine pyrimethamine, sulfadoxine pyrimethamine resistance

How to cite this article:
Yaro A. Mechanisms of sulfadoxine pyrimethamine resistance and health implication in Plasmodium falciparum malaria: A mini review. Ann Trop Med Public Health 2009;2:20-3
How to cite this URL:
Yaro A. Mechanisms of sulfadoxine pyrimethamine resistance and health implication in Plasmodium falciparum malaria: A mini review. Ann Trop Med Public Health [serial online] 2009 [cited 2020 Dec 3];2:20-3. Available from:

Malaria is one of the most important public health issues affecting humanity today.

The World Health Organization (WHO) estimates that 500 million new malaria infections occur worldwide with 110 million cases of illness and almost 2 million deaths with 25% of childhood deaths in Africa are associated with malaria. [1] It is caused by four species of malaria parasite are Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. Occasional infections with monkey parasites, such P. knowlesis, also occur.

Antimalarial chemotherapy remains the principal means of fighting malaria, yet current efforts are thwarted by the ever-increasing prevalence of drug-resistant Plasmodia.[3] The practice of malaria chemotherapy has been in operation over many centuries; however, currently we find ourselves with only handful of options for clinical utility. Resistance to all known antimalarial drugs, with the possible exception of artemisinin derivative, has been reported in several countries. [4] Increasing drug resistance has prompted several countries to change from Chloroquine (CQ) to other regimens as first-line treatment, usually with sulfadoxine pyrimethamine (SP), which is affordable, relative safe, and easy to administer.[5] However, resistance to SP was quick to develop in Southeast Asia, [6] while in Africa, SP resistance was low but just for some few years. [7] However, though late it has reached a critical level in some East and Central Africa, raising the fears of a potential public health disaster. [8],[9],[10],[11],[12]

This mini review summarizes recent advances in the understanding of SP resistance and its impact on the health management in Sub Saharan Africa where the burden of malaria is enormous.

SP and SP resistance (SPR)

SP is part of the class of antifolate combination drugs that acts through sequential and synergistic mechanism to block two key enzymes involved in folate synthesis.

Pyrimethamine inhibits the activity of dihydrofolate reductase (DHFR), while the sulfonamides and sulfones (in this case sulfadoxine) inhibit the activity of dihydopteroate synthase (DHPS). It is widely known as Fansidar; (Hoffman-La Roche) but is also sold in a variety of other commercial and generic forms. Sulfonamides were first found to be active against primate and bird malarias in the early 1940s and this activity was found to be reversed by p-amino benzoic acid (PABA), a substrate for DHPS. The basis of antimalarial activity of pyrimethamine is the ability to inhibit folate pathway based on their similar structure to pyrimidine derivative and the observation that folate antagonizes their action in vitro. The direct action of these compounds on malarial DHFR was later demonstrated. [13],[14] Unfortunately, resistance has emerged rapidly in settings were the drug was deployed [8],[9],[10],[11],[12] for example, in a study in north-eastern Tanzania, it was found that 45% of patients under the trial treated with SP failed to clear their parasitemia to below potency level on day 7. [38] Studies have shown that point mutations in the drug target confers resistance to SP. [15],[18],[19] It has been suggested that drug pharmacokinetic, cross-resistance between drugs, over usage of drugs, and inadequate treatment through inappropriate prescription or administration, non-compliance, or poor absorption play significant role in the emergence of resistance. [20],[21],[22],[23] In addition, the timing of the treatment in relation to initiation of an immune response has been hypothesized to have an important role in the development of resistance. Also, implicated are host immunity and level of transmission. [24],[25],[26]

Mechanism of SPR

The molecular targets of each of the drug component are the thymidylate synthase (TS) enzyme for pyrimethamine and 7, 8-dihydro-6-hydroxymethylpterin pyrophosphokinase (PPPK) enzyme for sulfadoxine.[27],[28],[29] These two enzymes are important for the folic acid biosynthesis pathway. Research has shown that resistances to SP are associated with distinct point mutations in DHFR-TS and PPK-DHPS genes. A point mutation in DHFR gene causing a Ser→Asn at codon 108 of the DHFR domain has been implicated in resistance, [30],[31],[32] while high level in vitro resistance has shown that mutations at residue 51 resulting in Asn?Ile, 59 (Cys→Arg), and/or 164 (Ile?Leu) confer some level of resistance. [33],[34],[35] Initially, it was thought that resistance to pyrimethamine conferred resistant to cycloguanil automatically, but it was later shown that the two are not linked. [31] Some mutations in the DFHR gene may result in reduced affinity of DFHR for either pyrimethamine or the biguanide alone, while other results in reduced affinity got both drugs. None of the mutations associated with DHFR appear to affect the function of the enzyme adversely. As only a single- or double-step mutation is required to move from ‘sensitivity’ to ‘resistance; the DHFR type of resistance occurs readily. [39]

With sulfadoxine, series of sequence analysis of the coding region of dihydropteroate synthase has identified a number of point mutations; all associated with in vitro resistance to sulfa drugs .The following mutations in the dihydropteroate synthase are associated with resistance to sulfadoxine based on in vitro analysis: an Ala→Gly mutation at codon 437 of the DHPS domain, while high levels of this drug component are associated with additional mutations at codon 581 (Ala→Gly), 436 (Ser→Phe), and 613 (Ala→Ser). [36],[37] Transfectional analysis in P. falciparum proved that dihydropteroate synthase mutations confer resistance to sulfonamides and sulfa drugs. [40],[41]

Current Status of SPR in Africa

Studies has shown that P. falciparum sensitivity to SP has been increasing in the continent, especially in East Africa where SP has been on large scale use [43],[44],[45] and in some parts of West Africa. [46] Currently, the parasitological failure rate on day 7 of treatment is about 13% in Malawi where SP has been the first-line drug since 1993, [47] although another study reported that contrary to expectation, SP has retained good efficacy as first-line antimalarial drug in Malawi, [52] Tanzania, reported of about 50% failure rate at one site. [48] A recent study in Kenya showed that resistance to SP has reached high levels in many but not all areas, [49] while another study showed a low sensitivity rate of 62.7% for SP in the treatment of non-severe P. falciparum malaria in children in high-transmission area in Western Kenya.[50] A study to analyze treatment outcome in a randomized, double-blind trial with SP and chlorproguanil-dapson efficacy in treating uncomplicated P. falciparum malaria in Malawian children, it was found that of the 84 pre-treatment samples of blood from patients with P. falciparum infection who were treated with SP, the clinical rate failure was high in the SP arm (20.1%) compared to the chlorproguanil-dapson arm (5.1%). This failure was attributed to mutation in the DHFR and DHPS genes. [51] In Gabon where SP and amodiaquine-artesunate (AQ/AS) have been adopted as first-line drugs, in trial to compare the efficacy of these combinations, it was reported that there was 26.1% treatment failures in the SP arm compared to 45.1% of the AQ arm. This means, SP is more efficacious than AQ while a multi-site study in Madagascar reported that antimalarial drug resistance (including SPR) remains low in CQR. [53]

More studies need to be undertaken in malaria endemic areas that have adopted SP as first-line drug regimen to really understand and evaluated factors that promote SPR.

SPR Impact on Health

Malaria is a huge public health problem in Africa and with most African countries adopting SP as first-line regimen for the treatment of malaria infection, SPR results in enormous public health burden because of prolonged or recurrent sickness and progression to severe malaria which is associated with increased hospitalization and deaths. Resistance, even at lower levels will lead to recrudescence of malaria infection that is associated with return of disease, prolonged or worsening of anemia, and fuels the transmission rate. As a result, health facilities become overwhelmed. Both out- and in-patients cases increase beyond the normal health facilities capacity.

It also has direct impact of the productive labor force [42] and on public health expenditure; for example in Eritrea, the average cost of treating uncomplicated malaria is about 2.00 USD and about 7.00 USD for severe cases. [42],[54]


Despite the extensive work been done on SPR, still more work needs to be done for understanding the molecular mechanism of combination mutations in the two genes: DHFR and DHPS; however, the factors promoting the development and transmission of these mutants are still to be elucidated. However, it is clear that these mutations can convert a clinical parasite from sensitive to resistant, although a universal marker of SP resistance has not been identified which will need collaborative network to achieve.

Drug resistance in human malaria infection is a major challenge and failure to understand the factors that contribute to resistance development and failure to understand the biological mechanism of resistance will have a devastating impact on our ability to deal with this life-threatening infection. This means that because most African countries have adopted SP as first-line regimen, therefore more studies need to be undertaken on factors that promote the SPR.

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Source of Support: None, Conflict of Interest: None

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