# Mechanisms of varied sensitivity of P. falciparum field isolates to the antimalarial drug pipeline

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $683,345

## Abstract

Summary
The treatment and control of malaria are seriously challenged by drug resistance. With widespread resistance
to older agents, artemisinin-based combination therapies (ACTs) are the mainstay for antimalarial treatment,
but ACT efficacy is threatened by resistance to artemisinins and partner drugs. New antimalarial drugs are
needed. Spearheaded by the Medicines for Malaria Venture (MMV), a robust pipeline of new lead antimalarial
compounds is under development. However, resistance to new antimalarial agents can be anticipated. In a
number of cases drug targets and resistance mechanisms have been identified, but studies have focused on
small numbers of P. falciparum laboratory strains. It is critical also to consider sensitivity to lead antimalarials of
fresh P. falciparum field isolates, especially isolates from Africa. In pilot studies we have identified important
variability in ex vivo sensitivity of fresh Ugandan P. falciparum isolates to lead antimalarial compounds. In
some cases this variability appears to be linked to mechanisms of resistance identified in the laboratory, but
not previously seen in field isolates. A better understanding of the extent of and mechanisms of decreased
sensitivity in African field isolates will be of great value in informing optimal development of next-generation
combination antimalarial therapies. This project will build on an ongoing collaboration between our group and
MMV, which has provided pilot data from Uganda, and another longstanding collaboration in Burkina Faso. Our
program will offer state-of-the-art assessment of ex vivo P. falciparum sensitivities linked to genotypic and
phenotypic characterization of field samples. We hypothesize that P. falciparum isolates from Uganda and
Burkina Faso will demonstrate varied sensitivity to lead antimalarial compounds, and that characterization of
genotypes and phenotypes of field isolates will identify shared resistance mechanisms and optimal
combination therapies. Our specific aims will be: (1) to characterize ex vivo sensitivity to lead antimalarial
compounds of P. falciparum field isolates, (2) to characterize genotypes of drug sensitivity outliers to identify
mediators of decreased sensitivity in field isolates, and (3) to characterize phenotypes of drug sensitivity
outliers to elucidate mechanisms of resistance of lead antimalarial compounds. Our studies will define
resistance mechanisms for the most important new compounds under development as antimalarials and inform
choices of optimal antimalarial drug combinations and the direction of continued drug discovery efforts.

## Key facts

- **NIH application ID:** 9921294
- **Project number:** 5R01AI139179-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Philip Jon Rosenthal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $683,345
- **Award type:** 5
- **Project period:** 2018-06-22 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921294

## Citation

> US National Institutes of Health, RePORTER application 9921294, Mechanisms of varied sensitivity of P. falciparum field isolates to the antimalarial drug pipeline (5R01AI139179-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9921294. Licensed CC0.

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