# Mapping Drug Resistance Genes in Plasmodium falciparum

> **NIH NIH R37** · TEXAS BIOMEDICAL RESEARCH INSTITUTE · 2021 · $923,047

## Abstract

The spread of resistance to artemisinin (ART) derivatives is an emerging public health crisis, but
also presents a valuable opportunity to understand the dynamics and evolution of resistance in
real-time, so we can better manage resistance in the future. My laboratory will focus on three
different, but complimentary research paths during the Merit extension period, with the central aim
of understanding the evolutionary dynamics, genetic architecture and mechanism of ARTresistance.
First, in collaboration with François Nosten, we will continue our long term monitoring of
parasite populations on the Thai-Burma border, by sequencing genomes from ~100 parasites per
year. We will document the change in frequency of kelch mutations over space and time, and
critically examine evidence that additional genes are selected by ART treatment. These analyses
will explore different statistical approaches for inferring adaptive evolution using longitudinal data
and will generate testable hypotheses about resistance evolution. Second, to compliment our
descriptive and statistical work and to test hypotheses generated, we will exploit our new-found
gene-editing skills using CRISPR/Cas9 methods. We will examine functional differences between
kelch alleles and experimentally investigate the role of additional genes selected by ART or
incriminated in genome-wide association or linkage analysis studies. These studies will involve (i)
editing of kelch alleles in parasite clones isolated from the Thailand-Burma border, (ii) phenotypic
analyses of fitness, resistance and genome-wide transcription in edited parasites to determine the
costs and benefits of different kelch alleles, (iii) functional analyses of additional candidate genes
implicated in ART-resistance evolution, and (iv) development of high-throughput CRISPR/Cas9
methods using pools of repair template sequences or guide sequences together with deep
sequence readout for gene and genome-wide analyses of loci underlying resistance. Lastly, we will
examine how single SNP changes in the kelch locus impact protein structure. This work will be
conducted with John Hart (UTHSCSA), with whom we have previously collaborated in studies of
schistosome drug resistance. We will determine crystal structures of wild-type and ART-resistant
kelch proteins encoded by different kelch alleles at high resolution. The molecules and biochemical
pathways involved in resistance are currently being identified. Co-crystallization of kelch and
interacting partner molecules will help to determine the mechanisms by which structural changes
impact molecular interactions and generate ART-resistance phenotypes. The genome sequences,
edited parasite clones, and crystal structures generated during this work will be made available to
the research community. The outcome of this research will be a detailed understanding of a drug
resistance selective sweep at population, genomic, functional and structural levels.

## Key facts

- **NIH application ID:** 10087843
- **Project number:** 5R37AI048071-20
- **Recipient organization:** TEXAS BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** Tim J Anderson
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $923,047
- **Award type:** 5
- **Project period:** 2000-09-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10087843

## Citation

> US National Institutes of Health, RePORTER application 10087843, Mapping Drug Resistance Genes in Plasmodium falciparum (5R37AI048071-20). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10087843. Licensed CC0.

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