Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline
ABSTRACT Malaria, especially Plasmodium falciparum infection, remains an enormous problem, and its treatment and control are seriously challenged by drug resistance. New antimalarial drugs are needed. To characterize the Medicines for Malaria Venture pipeline of antimalarials under development, we a...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-06-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.05236-22 |
| _version_ | 1797803453710336000 |
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| author | Oriana Kreutzfeld Patrick K. Tumwebaze Martin Okitwi Stephen Orena Oswald Byaruhanga Thomas Katairo Melissa D. Conrad Stephanie A. Rasmussen Jennifer Legac Ozkan Aydemir David Giesbrecht Barbara Forte Peter Campbell Alasdair Smith Hiroki Kano Samuel L. Nsobya Benjamin Blasco Maelle Duffey Jeffrey A. Bailey Roland A. Cooper Philip J. Rosenthal |
| author_facet | Oriana Kreutzfeld Patrick K. Tumwebaze Martin Okitwi Stephen Orena Oswald Byaruhanga Thomas Katairo Melissa D. Conrad Stephanie A. Rasmussen Jennifer Legac Ozkan Aydemir David Giesbrecht Barbara Forte Peter Campbell Alasdair Smith Hiroki Kano Samuel L. Nsobya Benjamin Blasco Maelle Duffey Jeffrey A. Bailey Roland A. Cooper Philip J. Rosenthal |
| author_sort | Oriana Kreutzfeld |
| collection | DOAJ |
| description | ABSTRACT Malaria, especially Plasmodium falciparum infection, remains an enormous problem, and its treatment and control are seriously challenged by drug resistance. New antimalarial drugs are needed. To characterize the Medicines for Malaria Venture pipeline of antimalarials under development, we assessed the ex vivo drug susceptibilities to 19 compounds targeting or potentially impacted by mutations in P. falciparum ABC transporter I family member 1, acetyl-CoA synthetase, cytochrome b, dihydroorotate dehydrogenase, elongation factor 2, lysyl-tRNA synthetase, phenylalanyl-tRNA synthetase, plasmepsin X, prodrug activation and resistance esterase, and V-type H+ ATPase of 998 fresh P. falciparum clinical isolates collected in eastern Uganda from 2015 to 2022. Drug susceptibilities were assessed by 72-h growth inhibition (half-maximum inhibitory concentration [IC50]) assays using SYBR green. Field isolates were highly susceptible to lead antimalarials, with low- to midnanomolar median IC50s, near values previously reported for laboratory strains, for all tested compounds. However, outliers with decreased susceptibilities were identified. Positive correlations between IC50 results were seen for compounds with shared targets. We sequenced genes encoding presumed targets to characterize sequence diversity, search for polymorphisms previously selected with in vitro drug pressure, and determine genotype-phenotype associations. We identified many polymorphisms in target genes, generally in <10% of isolates, but none were those previously selected in vitro with drug pressure, and none were associated with significantly decreased ex vivo drug susceptibility. Overall, Ugandan P. falciparum isolates were highly susceptible to 19 compounds under development as next-generation antimalarials, consistent with a lack of preexisting or novel resistance-conferring mutations in circulating Ugandan parasites. IMPORTANCE Drug resistance necessitates the development of new antimalarial drugs. It is important to assess the activities of compounds under development against parasites now causing disease in Africa, where most malaria cases occur, and to determine if mutations in these parasites may limit the efficacies of new agents. We found that African isolates were generally highly susceptible to the 19 studied lead antimalarials. Sequencing of the presumed drug targets identified multiple mutations in these genes, but these mutations were generally not associated with decreased antimalarial activity. These results offer confidence that the activities of the tested antimalarial compounds now under development will not be limited by preexisting resistance-mediating mutations in African malaria parasites. |
| first_indexed | 2024-03-13T05:21:04Z |
| format | Article |
| id | doaj.art-373b8efbdb7d4e76aea7095c81c6a1bf |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-03-13T05:21:04Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-373b8efbdb7d4e76aea7095c81c6a1bf2023-06-15T13:18:30ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-06-0111310.1128/spectrum.05236-22Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug PipelineOriana Kreutzfeld0Patrick K. Tumwebaze1Martin Okitwi2Stephen Orena3Oswald Byaruhanga4Thomas Katairo5Melissa D. Conrad6Stephanie A. Rasmussen7Jennifer Legac8Ozkan Aydemir9David Giesbrecht10Barbara Forte11Peter Campbell12Alasdair Smith13Hiroki Kano14Samuel L. Nsobya15Benjamin Blasco16Maelle Duffey17Jeffrey A. Bailey18Roland A. Cooper19Philip J. Rosenthal20University of California, San Francisco, San Francisco, California, USAInfectious Diseases Research Collaboration, Kampala, UgandaInfectious Diseases Research Collaboration, Kampala, UgandaInfectious Diseases Research Collaboration, Kampala, UgandaInfectious Diseases Research Collaboration, Kampala, UgandaInfectious Diseases Research Collaboration, Kampala, UgandaUniversity of California, San Francisco, San Francisco, California, USADominican University of California, San Rafael, California, USAUniversity of California, San Francisco, San Francisco, California, USAProgram in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USABrown University, Providence, Rhode Island, USAWellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, United KingdomWellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, United KingdomWellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, United KingdomMitsubishi Tanabe Pharma Corporation, Yokohama, JapanInfectious Diseases Research Collaboration, Kampala, UgandaMedicines for Malaria Venture, Geneva, SwitzerlandMedicines for Malaria Venture, Geneva, SwitzerlandBrown University, Providence, Rhode Island, USADominican University of California, San Rafael, California, USAUniversity of California, San Francisco, San Francisco, California, USAABSTRACT Malaria, especially Plasmodium falciparum infection, remains an enormous problem, and its treatment and control are seriously challenged by drug resistance. New antimalarial drugs are needed. To characterize the Medicines for Malaria Venture pipeline of antimalarials under development, we assessed the ex vivo drug susceptibilities to 19 compounds targeting or potentially impacted by mutations in P. falciparum ABC transporter I family member 1, acetyl-CoA synthetase, cytochrome b, dihydroorotate dehydrogenase, elongation factor 2, lysyl-tRNA synthetase, phenylalanyl-tRNA synthetase, plasmepsin X, prodrug activation and resistance esterase, and V-type H+ ATPase of 998 fresh P. falciparum clinical isolates collected in eastern Uganda from 2015 to 2022. Drug susceptibilities were assessed by 72-h growth inhibition (half-maximum inhibitory concentration [IC50]) assays using SYBR green. Field isolates were highly susceptible to lead antimalarials, with low- to midnanomolar median IC50s, near values previously reported for laboratory strains, for all tested compounds. However, outliers with decreased susceptibilities were identified. Positive correlations between IC50 results were seen for compounds with shared targets. We sequenced genes encoding presumed targets to characterize sequence diversity, search for polymorphisms previously selected with in vitro drug pressure, and determine genotype-phenotype associations. We identified many polymorphisms in target genes, generally in <10% of isolates, but none were those previously selected in vitro with drug pressure, and none were associated with significantly decreased ex vivo drug susceptibility. Overall, Ugandan P. falciparum isolates were highly susceptible to 19 compounds under development as next-generation antimalarials, consistent with a lack of preexisting or novel resistance-conferring mutations in circulating Ugandan parasites. IMPORTANCE Drug resistance necessitates the development of new antimalarial drugs. It is important to assess the activities of compounds under development against parasites now causing disease in Africa, where most malaria cases occur, and to determine if mutations in these parasites may limit the efficacies of new agents. We found that African isolates were generally highly susceptible to the 19 studied lead antimalarials. Sequencing of the presumed drug targets identified multiple mutations in these genes, but these mutations were generally not associated with decreased antimalarial activity. These results offer confidence that the activities of the tested antimalarial compounds now under development will not be limited by preexisting resistance-mediating mutations in African malaria parasites.https://journals.asm.org/doi/10.1128/spectrum.05236-22Plasmodium falciparumUgandan field isolatesantimalarialsdrug resistancegenotypic identificationmalaria |
| spellingShingle | Oriana Kreutzfeld Patrick K. Tumwebaze Martin Okitwi Stephen Orena Oswald Byaruhanga Thomas Katairo Melissa D. Conrad Stephanie A. Rasmussen Jennifer Legac Ozkan Aydemir David Giesbrecht Barbara Forte Peter Campbell Alasdair Smith Hiroki Kano Samuel L. Nsobya Benjamin Blasco Maelle Duffey Jeffrey A. Bailey Roland A. Cooper Philip J. Rosenthal Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline Microbiology Spectrum Plasmodium falciparum Ugandan field isolates antimalarials drug resistance genotypic identification malaria |
| title | Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline |
| title_full | Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline |
| title_fullStr | Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline |
| title_full_unstemmed | Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline |
| title_short | Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline |
| title_sort | susceptibility of ugandan plasmodium falciparum isolates to the antimalarial drug pipeline |
| topic | Plasmodium falciparum Ugandan field isolates antimalarials drug resistance genotypic identification malaria |
| url | https://journals.asm.org/doi/10.1128/spectrum.05236-22 |
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