Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance.
Multidrug-resistant Plasmodium falciparum parasites have emerged in Cambodia and neighboring countries in Southeast Asia, compromising the efficacy of first-line antimalarial combinations. Dihydroartemisinin + piperaquine (PPQ) treatment failure rates have risen to as high as 50% in some areas in th...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-02-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1010278 |
| _version_ | 1828215152291348480 |
|---|---|
| author | Jennifer L Small-Saunders Laura M Hagenah Kathryn J Wicht Satish K Dhingra Ioanna Deni Jonathan Kim Jeremie Vendome Eva Gil-Iturbe Paul D Roepe Monica Mehta Filippo Mancia Matthias Quick Margaret J Eppstein David A Fidock |
| author_facet | Jennifer L Small-Saunders Laura M Hagenah Kathryn J Wicht Satish K Dhingra Ioanna Deni Jonathan Kim Jeremie Vendome Eva Gil-Iturbe Paul D Roepe Monica Mehta Filippo Mancia Matthias Quick Margaret J Eppstein David A Fidock |
| author_sort | Jennifer L Small-Saunders |
| collection | DOAJ |
| description | Multidrug-resistant Plasmodium falciparum parasites have emerged in Cambodia and neighboring countries in Southeast Asia, compromising the efficacy of first-line antimalarial combinations. Dihydroartemisinin + piperaquine (PPQ) treatment failure rates have risen to as high as 50% in some areas in this region. For PPQ, resistance is driven primarily by a series of mutant alleles of the P. falciparum chloroquine resistance transporter (PfCRT). PPQ resistance was reported in China three decades earlier, but the molecular driver remained unknown. Herein, we identify a PPQ-resistant pfcrt allele (China C) from Yunnan Province, China, whose genotypic lineage is distinct from the PPQ-resistant pfcrt alleles currently observed in Cambodia. Combining gene editing and competitive growth assays, we report that PfCRT China C confers moderate PPQ resistance while re-sensitizing parasites to chloroquine (CQ) and incurring a fitness cost that manifests as a reduced rate of parasite growth. PPQ transport assays using purified PfCRT isoforms, combined with molecular dynamics simulations, highlight differences in drug transport kinetics and in this transporter's central cavity conformation between China C and the current Southeast Asian PPQ-resistant isoforms. We also report a novel computational model that incorporates empirically determined fitness landscapes at varying drug concentrations, combined with antimalarial susceptibility profiles, mutation rates, and drug pharmacokinetics. Our simulations with PPQ-resistant or -sensitive parasite lines predict that a three-day regimen of PPQ combined with CQ can effectively clear infections and prevent the evolution of PfCRT variants. This work suggests that including CQ in combination therapies could be effective in suppressing the evolution of PfCRT-mediated multidrug resistance in regions where PPQ has lost efficacy. |
| first_indexed | 2024-04-12T15:16:43Z |
| format | Article |
| id | doaj.art-c0f2898adda746c4b1fca32595599be4 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-12T15:16:43Z |
| publishDate | 2022-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-c0f2898adda746c4b1fca32595599be42022-12-22T03:27:36ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742022-02-01182e101027810.1371/journal.ppat.1010278Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance.Jennifer L Small-SaundersLaura M HagenahKathryn J WichtSatish K DhingraIoanna DeniJonathan KimJeremie VendomeEva Gil-IturbePaul D RoepeMonica MehtaFilippo ManciaMatthias QuickMargaret J EppsteinDavid A FidockMultidrug-resistant Plasmodium falciparum parasites have emerged in Cambodia and neighboring countries in Southeast Asia, compromising the efficacy of first-line antimalarial combinations. Dihydroartemisinin + piperaquine (PPQ) treatment failure rates have risen to as high as 50% in some areas in this region. For PPQ, resistance is driven primarily by a series of mutant alleles of the P. falciparum chloroquine resistance transporter (PfCRT). PPQ resistance was reported in China three decades earlier, but the molecular driver remained unknown. Herein, we identify a PPQ-resistant pfcrt allele (China C) from Yunnan Province, China, whose genotypic lineage is distinct from the PPQ-resistant pfcrt alleles currently observed in Cambodia. Combining gene editing and competitive growth assays, we report that PfCRT China C confers moderate PPQ resistance while re-sensitizing parasites to chloroquine (CQ) and incurring a fitness cost that manifests as a reduced rate of parasite growth. PPQ transport assays using purified PfCRT isoforms, combined with molecular dynamics simulations, highlight differences in drug transport kinetics and in this transporter's central cavity conformation between China C and the current Southeast Asian PPQ-resistant isoforms. We also report a novel computational model that incorporates empirically determined fitness landscapes at varying drug concentrations, combined with antimalarial susceptibility profiles, mutation rates, and drug pharmacokinetics. Our simulations with PPQ-resistant or -sensitive parasite lines predict that a three-day regimen of PPQ combined with CQ can effectively clear infections and prevent the evolution of PfCRT variants. This work suggests that including CQ in combination therapies could be effective in suppressing the evolution of PfCRT-mediated multidrug resistance in regions where PPQ has lost efficacy.https://doi.org/10.1371/journal.ppat.1010278 |
| spellingShingle | Jennifer L Small-Saunders Laura M Hagenah Kathryn J Wicht Satish K Dhingra Ioanna Deni Jonathan Kim Jeremie Vendome Eva Gil-Iturbe Paul D Roepe Monica Mehta Filippo Mancia Matthias Quick Margaret J Eppstein David A Fidock Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance. PLoS Pathogens |
| title | Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance. |
| title_full | Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance. |
| title_fullStr | Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance. |
| title_full_unstemmed | Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance. |
| title_short | Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance. |
| title_sort | evidence for the early emergence of piperaquine resistant plasmodium falciparum malaria and modeling strategies to mitigate resistance |
| url | https://doi.org/10.1371/journal.ppat.1010278 |
| work_keys_str_mv | AT jenniferlsmallsaunders evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT lauramhagenah evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT kathrynjwicht evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT satishkdhingra evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT ioannadeni evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT jonathankim evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT jeremievendome evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT evagiliturbe evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT pauldroepe evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT monicamehta evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT filippomancia evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT matthiasquick evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT margaretjeppstein evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance AT davidafidock evidencefortheearlyemergenceofpiperaquineresistantplasmodiumfalciparummalariaandmodelingstrategiestomitigateresistance |