Stepwise acquisition of pyrimethamine resistance in the malaria parasite
The spread of high-level pyrimethamine resistance in Africa threatens to curtail the therapeutic lifetime of antifolate antimalarials. We studied the possible evolutionary pathways in the evolution of pyrimethamine resistance using an approach in which all possible mutational intermediates were crea...
Saved in:
Main Authors: | , , , , , , , , |
---|---|
Other Authors: | |
Format: | Article |
Published: |
2018
|
Subjects: | |
Online Access: | https://repository.li.mahidol.ac.th/handle/123456789/28388 |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Institution: | Mahidol University |
id |
th-mahidol.28388 |
---|---|
record_format |
dspace |
spelling |
th-mahidol.283882018-09-13T14:17:43Z Stepwise acquisition of pyrimethamine resistance in the malaria parasite Elena R. Lozovsky Thanat Chookajorn Kyle M. Brown Mallika Imwong Philip J. Shaw Sumalee Kamchonwongpaisan Daniel E. Neafsey Daniel M. Weinreich Daniel L. Hartl Harvard University Mahidol University Thailand National Center for Genetic Engineering and Biotechnology Broad Institute Brown University Multidisciplinary The spread of high-level pyrimethamine resistance in Africa threatens to curtail the therapeutic lifetime of antifolate antimalarials. We studied the possible evolutionary pathways in the evolution of pyrimethamine resistance using an approach in which all possible mutational intermediates were created by site-directed mutagenesis and assayed for their level of drug resistance. The coding sequence for dihydrofolate reductase (DHFR) from the malaria parasite Plasmodium falciparum was mutagenized, and tests were carried out in Escherichia coli under conditions in which the endogenous bacterial enzyme was selectively inhibited. We studied 4 key amino acid replacements implicated in pyrimethamine resistance: N51I, C59R, S108N, and I164L. Using empirical estimates of the mutational spectrum in P. falciparum and probabilities of fixation based on the relative levels of resistance, we found that the predicted favored pathways of drug resistance are consistent with those reported in previous kinetic studies, as well as DHFR polymorphisms observed in natural populations. We found that 3 pathways account for nearly 90% of the simulated realizations of the evolution of pyrimethamine resistance. The most frequent pathway (S108N and then C59R, N51I, and I164L) accounts for more than half of the simulated realizations. Our results also suggest an explanation for why I164L is detected in Southeast Asia and South America, but not at significant frequencies in Africa. 2018-09-13T07:17:43Z 2018-09-13T07:17:43Z 2009-07-21 Article Proceedings of the National Academy of Sciences of the United States of America. Vol.106, No.29 (2009), 12025-12030 10.1073/pnas.0905922106 10916490 00278424 2-s2.0-67749098058 https://repository.li.mahidol.ac.th/handle/123456789/28388 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=67749098058&origin=inward |
institution |
Mahidol University |
building |
Mahidol University Library |
continent |
Asia |
country |
Thailand Thailand |
content_provider |
Mahidol University Library |
collection |
Mahidol University Institutional Repository |
topic |
Multidisciplinary |
spellingShingle |
Multidisciplinary Elena R. Lozovsky Thanat Chookajorn Kyle M. Brown Mallika Imwong Philip J. Shaw Sumalee Kamchonwongpaisan Daniel E. Neafsey Daniel M. Weinreich Daniel L. Hartl Stepwise acquisition of pyrimethamine resistance in the malaria parasite |
description |
The spread of high-level pyrimethamine resistance in Africa threatens to curtail the therapeutic lifetime of antifolate antimalarials. We studied the possible evolutionary pathways in the evolution of pyrimethamine resistance using an approach in which all possible mutational intermediates were created by site-directed mutagenesis and assayed for their level of drug resistance. The coding sequence for dihydrofolate reductase (DHFR) from the malaria parasite Plasmodium falciparum was mutagenized, and tests were carried out in Escherichia coli under conditions in which the endogenous bacterial enzyme was selectively inhibited. We studied 4 key amino acid replacements implicated in pyrimethamine resistance: N51I, C59R, S108N, and I164L. Using empirical estimates of the mutational spectrum in P. falciparum and probabilities of fixation based on the relative levels of resistance, we found that the predicted favored pathways of drug resistance are consistent with those reported in previous kinetic studies, as well as DHFR polymorphisms observed in natural populations. We found that 3 pathways account for nearly 90% of the simulated realizations of the evolution of pyrimethamine resistance. The most frequent pathway (S108N and then C59R, N51I, and I164L) accounts for more than half of the simulated realizations. Our results also suggest an explanation for why I164L is detected in Southeast Asia and South America, but not at significant frequencies in Africa. |
author2 |
Harvard University |
author_facet |
Harvard University Elena R. Lozovsky Thanat Chookajorn Kyle M. Brown Mallika Imwong Philip J. Shaw Sumalee Kamchonwongpaisan Daniel E. Neafsey Daniel M. Weinreich Daniel L. Hartl |
format |
Article |
author |
Elena R. Lozovsky Thanat Chookajorn Kyle M. Brown Mallika Imwong Philip J. Shaw Sumalee Kamchonwongpaisan Daniel E. Neafsey Daniel M. Weinreich Daniel L. Hartl |
author_sort |
Elena R. Lozovsky |
title |
Stepwise acquisition of pyrimethamine resistance in the malaria parasite |
title_short |
Stepwise acquisition of pyrimethamine resistance in the malaria parasite |
title_full |
Stepwise acquisition of pyrimethamine resistance in the malaria parasite |
title_fullStr |
Stepwise acquisition of pyrimethamine resistance in the malaria parasite |
title_full_unstemmed |
Stepwise acquisition of pyrimethamine resistance in the malaria parasite |
title_sort |
stepwise acquisition of pyrimethamine resistance in the malaria parasite |
publishDate |
2018 |
url |
https://repository.li.mahidol.ac.th/handle/123456789/28388 |
_version_ |
1763497077543796736 |