Defining drug resistance pathways in the malaria parasite

Hampering malaria control and elimination efforts is the resilient capacity of the parasite Plasmodium falciparum to develop resistance, including resistance to the presently recommended artemisinin based combination therapy (ACT). Unraveling the mechanisms of drug resistance becomes thus of utmost importance to avoid a devastating spread and shed light for future treatment improvement. Taking advantage of the advances in genetic tools, this project focus on the malaria parasite molecular factors that mediate resistance to antimalarial drugs and the parasite physiological changes and biological processes behind drug exposure, opening new avenues toward the design of novel, specific and more effective malaria therapeutics.

Funding Agency

Fundação Caloust Gulbenkian

ESCMID

MERIEUX Foundation

FCT

MESCyT/FONDOCyT

2CABraga

Project Reference

–

Project Members

Maria Isabel Veiga

Principal Investigator Project Leader

Nuno S. Osório

Principal Investigator

Claudia Fançony

Postdoctoral Researcher

Maria Pereira

PhD Student

Ruth Victoria Esho

PhD Student

Vitória da Cunha Baptista

PhD Student

Beatriz Velosa da Fonseca

MSc Student

Bruno José Ferreira Freitas

MSc Student

Claudia Alejandra Cabrera Federo

MSc Student

Main Project Outcomes

Publications

Plasmodium falciparum Drug Resistance Genes pfmdr1 and pfcrt In Vivo Co-Expression During Artemether-Lumefantrine Therapy.

Silva M, Malmberg M, Otienoburu SD, Björkman A, Ngasala B, Mårtensson A, Gil JP, Veiga MI.Front Pharmacol. 2022 May 24;13:868723. doi: 10.3389/fphar.2022.868723. eCollection 2022.PMID: 35685627

Chloroquine-susceptible and -resistant Plasmodium falciparum strains survive high chloroquine concentrations by becoming dormant but are eliminated by prolonged exposure.

Ursing J, Johns R, Aydin-Schmidt B, Calçada C, Kofoed PE, Ghanchi NK, Veiga MI, Rombo L.J Antimicrob Chemother. 2022 Mar 31;77(4):1005-1011. doi: 10.1093/jac/dkac008.PMID: 35137072

Expansion of a Specific Plasmodium falciparum PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport.

Calçada C, Silva M, Baptista V, Thathy V, Silva-Pedrosa R, Granja D, Ferreira PE, Gil JP, Fidock DA, Veiga MI.mBio. 2020 Dec 1;11(6):e02093-20. doi: 10.1128/mBio.02093-20.PMID: 33262257

Multigenic architecture of piperaquine resistance trait in Plasmodium falciparum.

Silva M, Calçada C, Teixeira M, Veiga MI, Ferreira PE.Lancet Infect Dis. 2020 Jan;20(1):26-27. doi: 10.1016/S1473-3099(19)30689-9.PMID: 31876497

Plasmodium falciparum K13 expression associated with parasite clearance during artemisinin-based combination therapy.

Silva M, Ferreira PE, Otienoburu SD, Calçada C, Ngasala B, Björkman A, Mårtensson A, Gil JP, Veiga MI.J Antimicrob Chemother. 2019 Jul 1;74(7):1890-1893. doi: 10.1093/jac/dkz098.PMID: 30869127

Plasmodium falciparum Plasmepsin 2 Duplications, West Africa.

Inoue J, Silva M, Fofana B, Sanogo K, Mårtensson A, Sagara I, Björkman A, Veiga MI, Ferreira PE, Djimde A, Gil JP.Emerg Infect Dis. 2018 Aug;24(8):1591-3. doi: 10.3201/eid2408.180370. Epub 2018 Aug 17.PMID: 29798744

Dosage of Single Low-Dose Primaquine to Stop Malaria Transmission.

Cruz M, Sánchez IM, Diaz J, Cuevas F, Silva M, Disla M, Ferreira PE, Veiga MI.J Infect Dis. 2018 May 5;217(11):1849-1850. doi: 10.1093/infdis/jiy108.PMID: 29529291

Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies.

Veiga MI, Dhingra SK, Henrich PP, Straimer J, Gnädig N, Uhlemann AC, Martin RE, Lehane AM, Fidock DA.Nat Commun. 2016 May 18;7:11553. doi: 10.1038/ncomms11553.PMID: 27189525

Complex polymorphisms in the Plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response.

Veiga MI, Osório NS, Ferreira PE, Franzén O, Dahlstrom S, Lum JK, Nosten F, Gil JP.Antimicrob Agents Chemother. 2014 Dec;58(12):7390-7. doi: 10.1128/AAC.03337-14. Epub 2014 Sep 29.PMID: 25267670

Single nucleotide polymorphisms in Plasmodium falciparum V type H(+) pyrophosphatase gene (pfvp2) and their associations with pfcrt and pfmdr1 polymorphisms.

Jovel IT, Ferreira PE, Veiga MI, Malmberg M, Mårtensson A, Kaneko A, Zakeri S, Murillo C, Nosten F, Björkman A, Ursing J.Infect Genet Evol. 2014 Jun;24:111-5. doi: 10.1016/j.meegid.2014.03.004. Epub 2014 Mar 20.PMID: 24657918

PhD thesis

2017 – 2022 PhD in Health Sciences, Miguel Silva, Fellowship: SFRH/BD/129769/2017.

“Defining molecular pathways in antimalarial drug resistance”.

2016 – 2021 PhD in Health Sciences, Carla Calçada, Fellowship:PD/BD/127826/2016

“Genetic determinants of malaria therapeutics’ cross resistance with novel compounds”.