Genome, Protozoan

Publication Title: 
Nucleic Acids Research. Supplement (2001)

We studied sequence polymorphism, expression level of pfmdr1 gene and drug sensitivity in mefloquine sensitive-strain as well as mefloquine-resistant clone/24 to understand underlying drug resistance mechanism. Mefloquine-resistant clone/24 exhibited decreased susceptibility to mefloquine, quinine, halofantrine and artemisinin and increased susceptibility to chloroquine. We analyzed sequence of pfmdr1 gene and found mutation in pfmdr1 on clone/24. Moreover, overexpression of mRNA level of pfmdr1 has been observed in mefloquine-resistant clone/24.

Author(s): 
Begum, Khurshida
Kim, Hye-Sook
Okuda, Yohei
Wataya, Yusuke
Kimura, Mikio
Huruta, Takahisa
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

With >1 million deaths annually, mostly among children in sub-Saharan Africa, malaria poses one of the most critical challenges in medicine today. Although introduction of the artemisinin class of antimalarial drugs has offered a temporary solution to the problem of drug resistance, new antimalarial drugs are needed to ensure effective control of the disease in the future. Herein, we have investigated members of the methionine aminopeptidase family as potential antimalarial targets.

Author(s): 
Chen, Xiaochun
Chong, Curtis R.
Shi, Lirong
Yoshimoto, Tadashi
Sullivan, David J.
Liu, Jun O.
Publication Title: 
Tropical medicine & international health: TM & IH

OBJECTIVES: To compare the efficacy and tolerability of dihydroartemisinin-piperaquine (DHA-PQP) with that of a 3-day regimen of mefloquine and artesunate (MAS3) for the treatment of uncomplicated falciparum malaria in Cambodia. METHOD: Randomized open-label non-inferiority study over 64 days. RESULTS: Four hundred and sixty-four patients were included in the study. The polymerase chain reaction genotyping-adjusted cure rates on day 63 were 97.5% (95% confidence interval, CI, 93.8-99.3) for DHA-PQP and 97.5% (95% CI, 93.8-99.3) for MAS3, P = 1.

Author(s): 
Janssens, B.
van Herp, M.
Goubert, L.
Chan, S.
Uong, S.
Nong, S.
Socheat, D.
Brockman, A.
Ashley, E. A.
Van Damme, W.
Publication Title: 
Current Opinion in Microbiology

The acquisition of drug resistance by Plasmodium falciparum has severely curtailed global efforts to control malaria. Our ability to define resistance has been greatly enhanced by recent advances in Plasmodium genetics and genomics. Sequencing and microarray studies have identified thousands of polymorphisms in the P. falciparum genome, and linkage disequilibrium analyses have exploited these to rapidly identify known and novel loci that influence parasite susceptibility to antimalarials such as chloroquine, quinine, and sulfadoxine-pyrimethamine.

Author(s): 
Ekland, Eric H.
Fidock, David A.
Publication Title: 
Nature

The human malaria parasite Plasmodium vivax is responsible for 25-40% of the approximately 515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P.

Author(s): 
Carlton, Jane M.
Adams, John H.
Silva, Joana C.
Bidwell, Shelby L.
Lorenzi, Hernan
Caler, Elisabet
Crabtree, Jonathan
Angiuoli, Samuel V.
Merino, Emilio F.
Amedeo, Paolo
Cheng, Qin
Coulson, Richard M. R.
Crabb, Brendan S.
Del Portillo, Hernando A.
Essien, Kobby
Feldblyum, Tamara V.
Fernandez-Becerra, Carmen
Gilson, Paul R.
Gueye, Amy H.
Guo, Xiang
Kang'a, Simon
Kooij, Taco W. A.
Korsinczky, Michael
Meyer, Esmeralda V.-S.
Nene, Vish
Paulsen, Ian
White, Owen
Ralph, Stuart A.
Ren, Qinghu
Sargeant, Tobias J.
Salzberg, Steven L.
Stoeckert, Christian J.
Sullivan, Steven A.
Yamamoto, Marcio M.
Hoffman, Stephen L.
Wortman, Jennifer R.
Gardner, Malcolm J.
Galinski, Mary R.
Barnwell, John W.
Fraser-Liggett, Claire M.
Publication Title: 
BMC genomics

BACKGROUND: Classical and quantitative linkage analyses of genetic crosses have traditionally been used to map genes of interest, such as those conferring chloroquine or quinine resistance in malaria parasites. Next-generation sequencing technologies now present the possibility of determining genome-wide genetic variation at single base-pair resolution. Here, we combine in vivo experimental evolution, a rapid genetic strategy and whole genome re-sequencing to identify the precise genetic basis of artemisinin resistance in a lineage of the rodent malaria parasite, Plasmodium chabaudi.

Author(s): 
Hunt, Paul
Martinelli, Axel
Modrzynska, Katarzyna
Borges, Sofia
Creasey, Alison
Rodrigues, Louise
Beraldi, Dario
Loewe, Laurence
Fawcett, Richard
Kumar, Sujai
Thomson, Marian
Trivedi, Urmi
Otto, Thomas D.
Pain, Arnab
Blaxter, Mark
Cravo, Pedro
Publication Title: 
Antimicrobial Agents and Chemotherapy

The combination of piperaquine and dihydroartemisinin has recently become the official first-line therapy in several Southeast Asian countries. The pharmacokinetic mismatching of these drugs, whose plasma half-lives are ~20 days and ~1 h, respectively, implies that recrudescent or new infections emerging shortly after treatment cessation will encounter piperaquine as a monotherapy agent. This creates substantial selection pressure for the emergence of resistance.

Author(s): 
Eastman, Richard T.
Dharia, Neekesh V.
Winzeler, Elizabeth A.
Fidock, David A.
Publication Title: 
Antimicrobial Agents and Chemotherapy

Multidrug-resistant Plasmodium falciparum malaria parasites pose a threat to effective drug control, even to artemisinin-based combination therapies (ACTs). Here we used linkage group selection and Solexa whole-genome resequencing to investigate the genetic basis of resistance to component drugs of ACTs. Using the rodent malaria parasite P. chabaudi, we analyzed the uncloned progeny of a genetic backcross between the mefloquine-, lumefantrine-, and artemisinin-resistant mutant AS-15MF and a genetically distinct sensitive clone, AJ, following drug treatment.

Author(s): 
Borges, Sofia
Cravo, Pedro
Creasey, Alison
Fawcett, Richard
Modrzynska, Katarzyna
Rodrigues, Louise
Martinelli, Axel
Hunt, Paul
Publication Title: 
Science (New York, N.Y.)

Evolving resistance to artemisinin-based compounds threatens to derail attempts to control malaria. Resistance has been confirmed in western Cambodia and has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CRs) after treatment. We used a two-phase strategy to identify genome region(s) underlying this ongoing selective event.

Author(s): 
Cheeseman, Ian H.
Miller, Becky A.
Nair, Shalini
Nkhoma, Standwell
Tan, Asako
Tan, John C.
Al Saai, Salma
Phyo, Aung Pyae
Moo, Carit Ler
Lwin, Khin Maung
McGready, Rose
Ashley, Elizabeth
Imwong, Mallika
Stepniewska, Kasia
Yi, Poravuth
Dondorp, Arjen M.
Mayxay, Mayfong
Newton, Paul N.
White, Nicholas J.
Nosten, François
Ferdig, Michael T.
Anderson, Timothy J. C.
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