Diverse evolutionary pathways challenge the use of collateral sensitivity as a strategy to suppress resistance
- Harvard T H Chan School of Public Health, United States
- University of California, San Diego, United States
- Massachusetts General Hospital, United States
- GlaxoSmithKline, Spain
- Broad Institute, United States
Abstract
Drug resistance remains a major obstacle to malaria control and eradication efforts, necessitating the development of novel therapeutic strategies to treat this disease. Drug combinations based on collateral sensitivity, wherein resistance to one drug causes increased sensitivity to the partner drug, have been proposed as an evolutionary strategy to suppress the emergence of resistance in pathogen populations. In this study, we explore collateral sensitivity between compounds targeting the Plasmodium dihydroorotate dehydrogenase (DHODH). We profiled the cross-resistance and collateral sensitivity phenotypes of several DHODH mutant lines to a diverse panel of DHODH inhibitors. We focus on one compound, TCMDC-125334, which was active against all mutant lines tested, including the DHODH C276Y line, which arose in selections with the clinical candidate DSM265. In six selections with TCMDC-125334, the most common mechanism of resistance to this compound was copy number variation of the dhodh locus, although we did identify one mutation, DHODH I263S, which conferred resistance to TCMDC-125334 but not DSM265. We found that selection of the DHODH C276Y mutant with TCMDC-125334 yielded additional genetic changes in the dhodh locus. These double mutant parasites exhibited decreased sensitivity to TCMDC-125334 and were highly resistant to DSM265. Finally, we tested whether collateral sensitivity could be exploited to suppress the emergence of resistance in the context of combination treatment by exposing wildtype parasites to both DSM265 and TCMDC-125334 simultaneously. This selected for parasites with a DHODH V532A mutation which were cross-resistant to both compounds and were as fit as the wildtype parent in vitro. The emergence of these cross-resistant, evolutionarily fit parasites highlights the mutational flexibility of the DHODH enzyme.
Data availability
The raw whole-genome sequencing data generated in this study have been submitted to the NCBI Sequence Read Archive database (https://www.ncbi.nlm.nih.gov/sra/) under accession number PRJNA689594. Sanger sequencing of the PCR amplified dhodh locus have been submitted to GenBank (NCBI) under accession numbers MZ571149-MZ571158.
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WGS of Plasmodium falciparum selected with DHODH inhibitorsNCBI Bioproject, PRJNA689594.
Article and author information
Author details
Elizabeth A Winzeler
Funding
National Institutes of Health (R01 AI093716)
- Rebecca EK Mandt
- Dyann F Wirth
- Amanda K Lukens
Bill and Melinda Gates Foundation (OPP1132451)
- Rebecca EK Mandt
- Maria Jose Lafuente-Monasterio
- Francisco Javier Gamo
- Dyann F Wirth
- Amanda K Lukens
National Institutes of Health (T32 GM008666)
- Madeline R Luth
ExxonMobil Foundation
- Rebecca EK Mandt
- Dyann F Wirth
- Amanda K Lukens
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Mandt et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Diverse evolutionary pathways challenge the use of collateral sensitivity as a strategy to suppress resistance
eLife 12:e85023.
https://doi.org/10.7554/eLife.85023
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