Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum.
<h4>Background</h4>Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. Ho...
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0019636&type=printable |
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| author | Marna S Costanzo Kyle M Brown Daniel L Hartl |
| author_facet | Marna S Costanzo Kyle M Brown Daniel L Hartl |
| author_sort | Marna S Costanzo |
| collection | DOAJ |
| description | <h4>Background</h4>Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness.<h4>Methodology/principal findings</h4>We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine.<h4>Conclusions/significance</h4>Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possible public health implications of these findings are discussed. |
| format | Article |
| id | doaj-art-06c78b61e5cd4f21b9df671d9cea8e7c |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-06c78b61e5cd4f21b9df671d9cea8e7c2025-08-20T03:25:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0165e1963610.1371/journal.pone.0019636Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum.Marna S CostanzoKyle M BrownDaniel L Hartl<h4>Background</h4>Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness.<h4>Methodology/principal findings</h4>We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine.<h4>Conclusions/significance</h4>Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possible public health implications of these findings are discussed.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0019636&type=printable |
| spellingShingle | Marna S Costanzo Kyle M Brown Daniel L Hartl Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum. PLoS ONE |
| title | Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum. |
| title_full | Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum. |
| title_fullStr | Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum. |
| title_full_unstemmed | Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum. |
| title_short | Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum. |
| title_sort | fitness trade offs in the evolution of dihydrofolate reductase and drug resistance in plasmodium falciparum |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0019636&type=printable |
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