estimation. Nucleic Acids Res. 37, W510eW514.
Blakeley, R.L. 1984. p 191-253, In Blakeley RL, Benkovics SJ (ed), Folates and Pteri-
dines, vol. 1, Wiley, New York, NY.
Brooks, D.R., Wang, P., Read, M., Watkins, W.M., Sims, P.F., Hyde, J.E., 1994. Sequence
variation of the hydroxymethyldihydropterin pyrophosphokinase: dihy-
dropteroate synthase gene in lines of the human malaria parasite, Plasmodium
falciparum, with differing resistance to sulfadoxine. Eur. J. Biochem. 224,
397e405.
Bwakura-Dangarembizi, M., Kendall, L., Bakeera-Kitaka, S., Nahirya-Ntege, P.,
Keishanyu, R., Nathoo, K., Spyer, M.J., Kekitiinwa, A., Lutaakome, J., Mhute, T.,
Kasirye, P., Munderi, P., Musiime, V., Gibb, D.M., Walker, A.S., Prendergast, A.J.,
Antiretroviral Research for Watoto (ARROW) Trial Team, 2014. A randomized
trial of prolonged co-trimoxazole in HIV-infected children in Africa. N. Engl. J.
Med. 370, 41e53.
Chauvin, P., Menard, S., Iriart, X., Nsango, S.E., Tchioffo, M.T., Abate, L., Awono-
Amb
en
e, P.H., Morlais, I., Berry, A., 2015. Prevalence of Plasmodium falciparum
parasites resistant to sulfadoxine/pyrimethamine in pregnant women in
Yaound
e, Cameroon: emergence of highly resistant pfdhfr/pfdhps alleles.
J. Antimicrob. Chemother. 70, 2566e2571.
Cowman, A.F., Morry, M.J., Biggs, B.A., Cross, G.A., Foote, S.J., 1988. Amino acid
changes linked to pyrimethamine resistance in the dihydrofolate reductase-
thymidylate synthase gene of Plasmodium falciparum. Proc. Natl. Acad. Sci. U.
S. A. 85, 9109e9113.
de Beer, T.A., Louw, A.I., Joubert, F., 2006. Elucidation of sulfadoxine resistance with
structural models of the bifunctional Plasmodium falciparum dihydropterin
pyrophosphokinase-dihydropteroate synthase. Bioorg. Med. Chem. 14,
4433e4443.
Diala, C.C., Pennas, T., Marin, C., Belay, K.A., 2013. Perceptions of intermittent pre-
ventive treatment of malaria in pregnancy (IPTp) and barriers to adherence in
Nasarawa and Cross River States in Nigeria. Malar. J. 12, 342.
Drug resistance maps. Accessed 17 March 2015. Mapping the Distribution of Resis-
tance Genes of Malaria in Africa. http://www.drugresistancemaps.org/ipti/.
Ekanem, O.J., Weisfeld, J.S., Salako, L.A., Nahlen, B.L., Ezedinachi, E.N., Walker, O.,
Breman, J.G., Laoye, O.J., Hedberg, K., 1990. Sensitivity of Plasmodium falcipa-
rum to chloroquine and sulfadoxine/pyrimethamine in Nigerian children. Bull.
World Health Organ 68, 45e52.
Falade, C.O., Yusuf, B.O., Fadero, F.F., Mokuolu, O.A., Hamer, D.H., Salako, L.A., 2007.
Intermittent preventive treatment with sulphadoxine-pyrimethamine is effec-
tive in preventing maternal and placental malaria in Ibadan, south-western
Nigeria. Malar. J. 6, 88.
Falade, C.O., Dada-Adegbola, H.O., Ogunkunle, O.O., Oguike, M.C., Nash, O.,
Ademowo, O.G., 2014. Evaluation of the comparative efficacy and safety of
artemether-lumefantrine, artesunate-amodiaquine and artesunate-
amodiaquine-chlorpheniramine (Artemoclo™) for the treatment of acute un-
complicated malaria in Nigerian children. Med. Princ. Pract. 23, 204e211 .
FMOH., 2005. Federal ministry of health, Nigeria, pp. 1e27. National Malaria Control
Programme in Nigeria. Annual Report.
Gesase, S., Gosling, R.D., Hashim, R., Ord, R., Naidoo, I., Madebe, R., Mosha, J.F.,
Joho, A., Mandia, V., Mrema, H., Mapunda, E., Savael, Z., Lemnge, M.,
Mosha, F.W., Greenwood, B., Roper, C., Chandramohan, D., 2009. High resistance
of Plasmodium falciparum to sulphadoxine/pyrimethamine in northern
Tanzania and the emergence of dhps resistance mutation at Codon 581. PLoS
One 4, e4569. http://dx.doi.org/10.1371/journal.pone.0 004569.
Happi, C.T., Gbotosho, G.O., Folarin, O.A., Akinboye, D.O., Yusuf, B.O., Ebong, O.O.,
Sowunmi, A., Kyle, D.E., Milhous, W., Wirth, D.F., Oduola, A.M., 2005. Poly-
morphisms in Plasmodium falciparum dhfr and dhps genes and age related
in vivo sulfadoxine-pyrimethamine resistance in malaria-infected patients from
Nigeria. Acta Trop. 95, 183e193.
Jelinek, T., Kilian, A.H., Curtis, J., Duraisingh, M.T., Kabagambe, G., von
Sonnenburg, F., Warhurst, D.C., 1999. Plasmodium falciparum: selection of
serine 108 of dihydrofolate reductase during treatment of uncomplicated ma-
laria with co-trimoxazole in Ugandan children. Am. J. Trop. Med. Hyg. 61,
125e130.
Kelley, L.A., Mezulis, S., Yates, C.M., Wass, M.N., Sternberg, M.J., 2015. The Phyre2
web portal for protein modeling, prediction and analysis. Nat. Protoc. 10,
845e858.
Lawrence, M.C., Iliades, P., Fernley, R.T., Berglez, J., Pilling, P.A., Macreadie, I.G., 2005.
The three-dimensional structure of the bifunctional 6-hydroxymethyl-7, 8-
dihydropterin pyrophosphokinase/dihydropteroate synthase of Saccharomyces
cerevisiae. J. Mol. Biol. 348, 655e670.
Menendez, C., 1995. Malaria during pregnancy: a priority area of malaria research
and control. Parasitol. Today 11, 178e183.
Menendez, C., Bardaji, A., Sigauque, B., Sanz, S., Aponte, J.J., Mabunda, S., Alonso, P.L.,
2010. Malaria prevention with IPTp during pregnancy reduces neonatal mor-
tality. PLoS One 5, e9438. http://dx.doi.org/10.1371/journal.pone.0009438.
Minja, D.T., Schmiegelow, C., Mmbando, B., Bostr
€
om, S., Oesterholt, M.,
Magistrado, P., Pehrson, C., John, D., Salanti, A ., Luty, A.J., Lemnge, M.,
Theander, T., Lusingu, J., Alifrangis, M., 2013. Plasmodium falciparum mutant
haplotype infection during pregnancy associated with reduced birthweight,
Tanzania. Emerg. Infect. Dis. 19 http://dx.doi.org/10.3201/eid1909.130133.
Mockenhaupt, F.P., Bedu-Addo, G., Eggelte, T.A., Hommerich, L., Holmberg, V., von
Oertzen, C., Bienzle, U., 2008. Rapid increase in the prevalence of sulphadoxine-
pyrimethamine resistance among Plasmodium falciparum isolated from preg-
nant women in Ghana. J. Infect. Dis. 198, 1545e1549.
Naidoo, I., Roper, C., 2011. Drug resistance maps to guide intermittent preventive
treatment of malaria in African infants. Parasitology 138, 1469e1479.
Naidoo, I., Roper, C., 2013. Mapping ‘partially resistant’, fully resistant’ and ‘super
resistant’ malaria. Trends Parasitol. 29, 505e 515.
Omar, S.A., Bakari, A., Owiti, A., Adagu, I.S., Warhurst, D.C., 2001. Co-trimoxazole
compared with sulfadoxine-pyrimethamine in the treatment of uncomplicated
malaria in Kenyan children. Trans. R. Soc. Trop. Med. Hyg. 95, 657e660.
Onoka, C.A., Hanson, K., Onwujekwe, O.E., 2012. Low coverage of intermittent
preventive treatment for malaria in pregnancy in Nigeria: demand-side in-
fluences. Malar. J. 11, 82 .
Onwujekwe, O.C., Soremekun, R.O., Uzochukwu, B., Shu, E., Onwujekwe, O., 2012.
Patterns of case management and chemoprevention for malaria-in-pregnancy
by public and private sector health providers in Enugu state, Nigeria. BMC
Res. Notes 5, 211.
Oyibo, W.A., Agomo, C.O., 2011. Scaling up of intermittent preventive treatment of
malaria in pregnancy using sulphadoxine-pyrimethamine: prospects and
challenges. Matern. Child. Health J. 15, 542e552.
Pearce, R., Pota, H., Evehe, M.B., B
^
a el-, H., Mombo-Ngoma, G., Malisa, A.L., Ord, R.,
Inojosa, W., Matondo, A., Diallo, D.A., Mbacham, W., van den Broek, I.V.,
Swarthout, T.D., Getachew, A., Dejene, S., Grobusch, M.P., Njie, F., Dunyo, S.,
Kweku, M., Owusu-Agyei, S., Chandramohan, D., Bonnet, M., Guthmann, J.P.,
Clarke, S., Barnes, K.I., Streat, E., Katokele, S.T., Uusiku, P., Agboghoroma, C.O.,
Elegba, O.Y., Ciss
e, B., A-Elbasit, I.E., Giha, H.A., Kachur, S.P., Lynch, C.,
Rwakimari, J.B., Chanda, P., Hawela, M., Sharp, B., Naidoo, I., Roper, C., 2009.
Multiple origins and regional dispersal of resistant dhps in African P. falciparum
malaria. PLoS Med. 6, e1000055. http://dx.doi.org/10.1371/
journal.pmed.1000055.
Pearce, R.J., Drakeley, C., Chandramohan, D., Mosha, F., Roper, C., 2003. Molecular
determination of point mutation haplotypes in the dihydrofolate reductase and
dihydropteroate synthase of Plasmodium falciparum in three districts of
northern Tanzania. Antimicrob. Agents Chemother. 47, 1347e1354.
Pemble 4th, C.W., Mehta, P.K., Mehra, S., Li, Z., Nourse, A., Lee, R.E., White, S.W.,
2010. Crystal structure of the 6-hydroxymethyl-7,8-dihydropterin pyrophos-
phokinasedihydropteroate synthase bifunctional enzyme from Francisella
tularensis. PLoS One 5 (11), e14165. http://dx.doi.org/10.1371/
journal.pone.0014165.
Pires, D.E., Ascher, D.B., Blundell, T.L., 2014. DUET: a server for predicting effects of
mutations on protein stability using an integrated computational approach.
Nucleic Acids Res. 42, W314eW319.
Plasmoview. Accessed 3 September 2015. http://pathogenseq.lshtm.ac.uk/
plasmoview.
Plowe, C.V., Djimde, A., Bouare, M., Doumbo, O., Wellems, T.E., 1995. Pyrimethamine
and proguanil resistance-conferring mutations in Plasmodium falciparum
dihydrofolate reductase: polymerase chain reaction methods for surveillance in
Africa. Am. J. Trop. Med. Hyg. 52, 565e568.
Plowe, C.V., Cortese, J.F., Djimde, A., Nwanyanwu, O.C., Watkins, W.M.,
Winstanley, P.A., Estrada-Franco, J.G., Mollinedo, R.E., Avila, J.C., Cespedes, J.L.,
Carter, D., Doumbo, O.K., 1997. Mutations in Plasmodium falciparum dihy-
drofolate reductase and dihydropteroate synthase and epidemiologic patterns
of pyrimethamine-sulfadoxine use and resistance. J. Infect. Dis. 176, 1590e1596.
Shulman, C.E., Dorman, E.K., Cutts, F., Kawuondo, K., Bulmer, J.N., Peshu, N.,
Marsh, K., 1999. Intermittent sulphadoxine-pyrimethamine to prevent severe
anaemia secondary to malaria in pregnancy: a randomised placebo-controlled
trial. Lancet 353, 632e636.
Snounou, G., Viriyakosol, S., Zhu, X.P., Jarra, W., Pinheiro, L., do Rosario, V.E.,
Thaithong, S., Brown, K.N., 1993. High sensitivity of detection of human malaria
parasites by the use of nested polymerase chain reaction. Mol. Biochem. Para-
sitol 61, 315e320.
Sutherland, C.J., Fifer, H., Pearce, R.J., bin Reza, F., Nicholas, M., Haustein, T., Njimgye-
Tekumafor, N.E., Doherty, J.F., Gothard, P., Polley, S.D., Chiodini, P.L., 2009. Novel
pfdhps haplotypes among imported cases of Plasmodium falciparum malaria in
the United Kingdom. Antimicrob. Agents Chemother. 53, 3405e3410.
Tahar, R., Basco, L.K., 2007. Molecular epidemiology of malaria in Cameroon XXVII.
Clinical and parasitological response to sulfadoxine-pyrimethamine treatment
and Plasmodium falciparum dihydrofolate reductase and dihydropteroate
synthase alleles in Cameroonian children. Acta Trop. 103, 81e98.
Triglia, T., Cowman, A.F., 1994. Primary structure and expression of the dihy-
dropteroate synthetase gene of Plasmodium falciparum. Proc. Natl. Acad. Sci. U.
S. A. 91, 7149e71 53.
Triglia, T., Menting, J.G.T., Wilson, C., Cowman, A.F., 1997. Mutations in dihy-
dropteroate synthase are responsible for sulfone and sulfonamide resistance in
Plasmodium falciparum. Proc. Natl. Acad. Sci. U. S. A. 94, 13944e13949.
Triglia, T., Wang, P., Sims, P.F.G., Hyde, J.E., Cowman, A.F., 1998. Allelic exchange at
the endogenous genomic locus in Plasmodium falciparum proves the role of
dihydropteroate synthase in sulfadoxine-resistant malaria. EMBO J. 17,
3807e3815.
Ugwu, E.O., Iferikigwe, E.S., Obi, S.N., Ugwu, A .O., Agu, P.U., Okezie, O.A., 2013. Anti-
malaria prescription in pregnancy among general practitioners in Enugu state,
south east Nigeria. Niger. Med. J. 54, 96e99. http://dx.doi.org/10.4103/0300-
1652.110038.
Walter, R.D., 1991. Folate metabolism as a target for chemotherapy of malaria. In:
Coombs, G.H., North, M.J. (Eds.), Biochemical Protozoology. Taylor Francis,
London, pp. 560e568.
Wang, P., Lee, C.S., Bayoumi, R., Djimde, A ., Doumbo, O., Swedberg, G., Dao, L.D.,
Mshinda, H., Tanner, M., Watkins, W.M., Sims, P.F., Hyde, J.E., 1997. Resistance to
antifolates in Plasmodium falciparum monitored by sequence analysis of
M.C. Oguike et al. / International Journal for Parasitology: Drugs and Drug Resistance 6 (2016) 220 e229228