TY - JOUR
T1 - Lumefantrine attenuates Plasmodium falciparum artemisinin resistance during the early ring stage
AU - Kümpornsin, Krittikorn
AU - Loesbanluechai, Duangkamon
AU - de Cozar, Cristina
AU - Kotanan, Namfon
AU - Chotivanich, Kesinee
AU - White, Nicholas J.
AU - Wilairat, Prapon
AU - Gomez-Lorenzo, Maria G.
AU - Gamo, Francisco Javier
AU - Sanz, Laura Maria
AU - Lee, Marcus C. S.
AU - Chookajorn, Thanat
N1 - Funding Information:
The work was supported by the Tres Cantos Open Lab Foundation, Wellcome ( 206194 ), the Bill and Melinda Gates Foundation ( OPP1054480 ), Newton Advanced Fellowship under The Thailand Research Fund-Royal Society ( DBG5980010 ) and the Faculty of Tropical Medicine, Mahidol University . DL was supported by Royal Golden Jubilee Ph.D. Program (Thailand Research Fund) and TRF-Newton Fund PhD Placement for Scholars (Thailand Research Fund and Newton Fund, United Kingdom).
Copyright:
© 2021 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology.
PY - 2021/12
Y1 - 2021/12
N2 - Emerging artemisinin resistance in Plasmodium falciparum malaria has the potential to become a global public health crisis. In Southeast Asia, this phenomenon clinically manifests in the form of delayed parasite clearance following artemisinin treatment. Reduced artemisinin susceptibility is limited to the early ring stage window, which is sufficient to allow parasites to survive the short half-life of artemisinin exposure. A screen of known clinically-implemented antimalarial drugs was performed to identify a drug capable of enhancing the killing activity of artemisinins during this critical resistance window. As a result, lumefantrine was found to increase the killing activity of artemisinin against an artemisinin-resistant clinical isolate harboring the C580Y kelch13 mutation. Isobologram analysis revealed synergism during the early ring stage resistance window, when lumefantrine was combined with artemether, an artemisinin derivative clinically partnered with lumefantrine. These findings suggest that lumefantrine should be clinically explored as a partner drug in artemisinin-based combination therapies to control emerging artemisinin resistance.
AB - Emerging artemisinin resistance in Plasmodium falciparum malaria has the potential to become a global public health crisis. In Southeast Asia, this phenomenon clinically manifests in the form of delayed parasite clearance following artemisinin treatment. Reduced artemisinin susceptibility is limited to the early ring stage window, which is sufficient to allow parasites to survive the short half-life of artemisinin exposure. A screen of known clinically-implemented antimalarial drugs was performed to identify a drug capable of enhancing the killing activity of artemisinins during this critical resistance window. As a result, lumefantrine was found to increase the killing activity of artemisinin against an artemisinin-resistant clinical isolate harboring the C580Y kelch13 mutation. Isobologram analysis revealed synergism during the early ring stage resistance window, when lumefantrine was combined with artemether, an artemisinin derivative clinically partnered with lumefantrine. These findings suggest that lumefantrine should be clinically explored as a partner drug in artemisinin-based combination therapies to control emerging artemisinin resistance.
KW - Artemisinin
KW - Drug resistance
KW - Isobologram
KW - Lumefantrine
KW - Malaria
UR - http://www.scopus.com/inward/record.url?scp=85117199589&partnerID=8YFLogxK
U2 - 10.1016/j.ijpddr.2021.09.005
DO - 10.1016/j.ijpddr.2021.09.005
M3 - Article
C2 - 34673330
AN - SCOPUS:85117199589
SN - 2211-3207
VL - 17
SP - 186
EP - 190
JO - International Journal for Parasitology: Drugs and Drug Resistance
JF - International Journal for Parasitology: Drugs and Drug Resistance
ER -