Exploration of the Resistome and Druggable Genome Reveals New Mechanisms of Drug Resistance and Antimalarial Targets
Plasmodium parasites, the causative agent of malaria infections, rapidly evolve drug resistance and escape detection by the human immune response via the incredible mutability of its genome. Understanding the genetic mechanisms by which Plasmodium parasites develop antimalarial resistance is essenti...
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2018-11-01
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Series: | Microbiology Insights |
Online Access: | https://doi.org/10.1177/1178636118808529 |
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doaj-3526a334d1f44f278d239a312776e2442020-11-25T02:52:21ZengSAGE PublishingMicrobiology Insights1178-63612018-11-011110.1177/1178636118808529Exploration of the Resistome and Druggable Genome Reveals New Mechanisms of Drug Resistance and Antimalarial TargetsAnnie Cowell0Elizabeth Winzeler1Division of Infectious Diseases, Department of Medicine, University of California, San Diego, San Diego, CA, USADivision of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California, San Diego, San Diego, CA, USAPlasmodium parasites, the causative agent of malaria infections, rapidly evolve drug resistance and escape detection by the human immune response via the incredible mutability of its genome. Understanding the genetic mechanisms by which Plasmodium parasites develop antimalarial resistance is essential to understanding why most drugs fail in the clinic and designing the next generation of therapies. A systematic genomic analysis of 262 Plasmodium falciparum clones with stable in vitro resistance to 37 diverse compounds with potent antimalarial activity was undertaken with the main goal of identifying new drug targets. Despite several challenges inherent to this method of in vitro drug resistance generation followed by whole genome sequencing, the study was able to identify a likely drug target or resistance gene for every compound for which resistant parasites could be generated. Known and novel P falciparum resistance mediators were discovered along with several new promising antimalarial drug targets. Surprisingly, gene amplification events contributed to one-third of the drug resistance acquisition events. The study can serve as a model for drug discovery and resistance analyses in other similar microbial pathogens amenable to in vitro culture.https://doi.org/10.1177/1178636118808529 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Annie Cowell Elizabeth Winzeler |
spellingShingle |
Annie Cowell Elizabeth Winzeler Exploration of the Resistome and Druggable Genome Reveals New Mechanisms of Drug Resistance and Antimalarial Targets Microbiology Insights |
author_facet |
Annie Cowell Elizabeth Winzeler |
author_sort |
Annie Cowell |
title |
Exploration of the Resistome and Druggable Genome Reveals New Mechanisms of Drug Resistance and Antimalarial Targets |
title_short |
Exploration of the Resistome and Druggable Genome Reveals New Mechanisms of Drug Resistance and Antimalarial Targets |
title_full |
Exploration of the Resistome and Druggable Genome Reveals New Mechanisms of Drug Resistance and Antimalarial Targets |
title_fullStr |
Exploration of the Resistome and Druggable Genome Reveals New Mechanisms of Drug Resistance and Antimalarial Targets |
title_full_unstemmed |
Exploration of the Resistome and Druggable Genome Reveals New Mechanisms of Drug Resistance and Antimalarial Targets |
title_sort |
exploration of the resistome and druggable genome reveals new mechanisms of drug resistance and antimalarial targets |
publisher |
SAGE Publishing |
series |
Microbiology Insights |
issn |
1178-6361 |
publishDate |
2018-11-01 |
description |
Plasmodium parasites, the causative agent of malaria infections, rapidly evolve drug resistance and escape detection by the human immune response via the incredible mutability of its genome. Understanding the genetic mechanisms by which Plasmodium parasites develop antimalarial resistance is essential to understanding why most drugs fail in the clinic and designing the next generation of therapies. A systematic genomic analysis of 262 Plasmodium falciparum clones with stable in vitro resistance to 37 diverse compounds with potent antimalarial activity was undertaken with the main goal of identifying new drug targets. Despite several challenges inherent to this method of in vitro drug resistance generation followed by whole genome sequencing, the study was able to identify a likely drug target or resistance gene for every compound for which resistant parasites could be generated. Known and novel P falciparum resistance mediators were discovered along with several new promising antimalarial drug targets. Surprisingly, gene amplification events contributed to one-third of the drug resistance acquisition events. The study can serve as a model for drug discovery and resistance analyses in other similar microbial pathogens amenable to in vitro culture. |
url |
https://doi.org/10.1177/1178636118808529 |
work_keys_str_mv |
AT anniecowell explorationoftheresistomeanddruggablegenomerevealsnewmechanismsofdrugresistanceandantimalarialtargets AT elizabethwinzeler explorationoftheresistomeanddruggablegenomerevealsnewmechanismsofdrugresistanceandantimalarialtargets |
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1724730586340261888 |