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Journal article
Associations between Varied Susceptibilities to PfATP4 Inhibitors and Genotypes in Ugandan Plasmodium falciparum Isolates
Antimicrobial agents and chemotherapy, v 65(10), pp e0077121-e0077121
17 Sep 2021
PMID: 34339273
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Among novel compounds under recent investigation as potential new antimalarial drugs are three independently developed inhibitors of the Plasmodium falciparum P-type ATPase (PfATP4): KAE609 (cipargamin), PA92, and SJ733. We assessed
susceptibilities to these compounds of 374 fresh P. falciparum isolates collected in Tororo and Busia districts, Uganda, from 2016 to 2019. Median IC
s were 65 nM for SJ733, 9.1 nM for PA92, and 0.5 nM for KAE609. Sequencing of
for 218 of these isolates demonstrated many nonsynonymous single nucleotide polymorphisms; the most frequent mutations were G1128R (69% of isolates mixed or mutant), Q1081K/R (68%), G223S (25%), N1045K (16%), and D1116G/N/Y (16%). The G223S mutation was associated with decreased susceptibility to SJ733, PA92, and KAE609. The D1116G/N/Y mutations were associated with decreased susceptibility to SJ733, and the presence of mutations at both codons 223 and 1116 was associated with decreased susceptibility to PA92 and SJ733. In all of these cases, absolute differences in susceptibilities of wild-type (WT) and mutant parasites were modest. Analysis of clones separated from mixed field isolates consistently identified mutant clones as less susceptible than WT. Analysis of isolates from other sites demonstrated the presence of the G223S and D1116G/N/Y mutations across Uganda. Our results indicate that malaria parasites circulating in Uganda have a number of polymorphisms in PfATP4 and that modestly decreased susceptibility to PfATP4 inhibitors is associated with some mutations now present in Ugandan parasites.
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Details
- Title
- Associations between Varied Susceptibilities to PfATP4 Inhibitors and Genotypes in Ugandan Plasmodium falciparum Isolates
- Creators
- Oriana Kreutzfeld - University of California, San FranciscoStephanie A Rasmussen - Dominican University of CaliforniaAarti A Ramanathan - Drexel UniversityPatrick K Tumwebaze - Infectious Diseases Research CollaborationOswald Byaruhanga - Infectious Diseases Research CollaborationThomas Katairo - Infectious Diseases Research CollaborationVictor Asua - Infectious Diseases Research CollaborationMartin Okitwi - Infectious Diseases Research CollaborationStephen Orena - Infectious Diseases Research CollaborationJennifer Legac - University of California, San FranciscoMelissa D Conrad - University of California, San FranciscoSamuel L Nsobya - Infectious Diseases Research CollaborationOzkan Aydemir - Brown UniversityJeffrey Bailey - Brown UniversityMaelle Duffey - Medicines for Malaria VentureBrett R Bayles - Dominican University of CaliforniaAkhil B Vaidya - Drexel UniversityRoland A Cooper - Dominican University of CaliforniaPhilip J Rosenthal - University of California, San Francisco
- Publication Details
- Antimicrobial agents and chemotherapy, v 65(10), pp e0077121-e0077121
- Publisher
- American Society for Microbiology (ASM)
- Grant note
- U19AI089674 / HHS | National Institutes of Health (NIH) R01 AI075045 / NIAID NIH HHS R01 AI132508 / NIAID NIH HHS R01 AI139179 / NIAID NIH HHS R01AI132508 / HHS | National Institutes of Health (NIH) RD/15/0001 / Medicines for Malaria Venture (MMV) U19 AI089674 / NIAID NIH HHS R01AI075045 / HHS | National Institutes of Health (NIH)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000702142700035
- Scopus ID
- 2-s2.0-85115144298
- Other Identifier
- 991019168557604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy