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.
Reviewing Editor
- Christine Clayton, Centre for Molecular Biology of Heidelberg University (ZMBH), retired, Germany
Version history
- Received: November 18, 2022
- Accepted: September 21, 2023
- Accepted Manuscript published: September 22, 2023 (version 1)
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
Further reading
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Groups of animals inhabit vastly different sensory worlds, or umwelten, which shape fundamental aspects of their behaviour. Yet the sensory ecology of species is rarely incorporated into the emerging field of collective behaviour, which studies the movements, population-level behaviours, and emergent properties of animal groups. Here, we review the contributions of sensory ecology and collective behaviour to understanding how animals move and interact within the context of their social and physical environments. Our goal is to advance and bridge these two areas of inquiry and highlight the potential for their creative integration. To achieve this goal, we organise our review around the following themes: (1) identifying the promise of integrating collective behaviour and sensory ecology; (2) defining and exploring the concept of a ‘sensory collective’; (3) considering the potential for sensory collectives to shape the evolution of sensory systems; (4) exploring examples from diverse taxa to illustrate neural circuits involved in sensing and collective behaviour; and (5) suggesting the need for creative conceptual and methodological advances to quantify ‘sensescapes’. In the final section, (6) applications to biological conservation, we argue that these topics are timely, given the ongoing anthropogenic changes to sensory stimuli (e.g. via light, sound, and chemical pollution) which are anticipated to impact animal collectives and group-level behaviour and, in turn, ecosystem composition and function. Our synthesis seeks to provide a forward-looking perspective on how sensory ecologists and collective behaviourists can both learn from and inspire one another to advance our understanding of animal behaviour, ecology, adaptation, and evolution.
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Changes in an organism’s environment, genome, or gene expression patterns can lead to changes in its metabolism. The metabolic phenotype can be under selection and contributes to adaptation. However, the networked and convoluted nature of an organism’s metabolism makes relating mutations, metabolic changes, and effects on fitness challenging. To overcome this challenge, we use the long-term evolution experiment (LTEE) with E. coli as a model to understand how mutations can eventually affect metabolism and perhaps fitness. We used mass spectrometry to broadly survey the metabolomes of the ancestral strains and all 12 evolved lines. We combined this metabolic data with mutation and expression data to suggest how mutations that alter specific reaction pathways, such as the biosynthesis of nicotinamide adenine dinucleotide, might increase fitness in the system. Our work provides a better understanding of how mutations might affect fitness through the metabolic changes in the LTEE and thus provides a major step in developing a complete genotype–phenotype map for this experimental system.
