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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $730,245

## Abstract

Project Summary
With widespread resistance of malaria parasites to older agents, artemisinin-based combination therapies are
the mainstay for antimalarial treatment, but 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 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. With these
data, genotypic and additional phenotypic analysis can allow identification of mechanisms underlying varied
susceptibility, as we have described for multiple compounds to date, informing optimal development of next-
generation combination antimalarials. This application seeks continued funding for a project characterizing
susceptibilities of malaria parasites isolated in Uganda and Burkina Faso to lead antimalarials under
development. We offer state-of-the-art assessment of ex vivo P. falciparum susceptibilities linked to high
throughput genotypic characterization to improve our understanding of mechanisms of drug action and
resistance. As supported by data generated to date, we hypothesize that African P. falciparum isolates will
demonstrate varied sensitivity to lead antimalarial compounds, and that characterization of genotypes and
phenotypes of field isolates will identify shared resistance mechanisms and guide selection of optimal
combination therapies. These results will be of great value as we develop next-generation combination
antimalarials and continue efforts toward discovery of additional novel compounds. Our specific aims will be:
(1) to characterize ex vivo susceptibilities to lead antimalarial compounds of P. falciparum field isolates, (2) to
characterize genotypes to identify mediators of decreased susceptibility in field isolates to lead antimalarial
compounds, 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:** 10734407
- **Project number:** 2R01AI139179-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Philip Jon Rosenthal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $730,245
- **Award type:** 2
- **Project period:** 2018-06-22 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10734407

## Citation

> US National Institutes of Health, RePORTER application 10734407, Mechanisms of varied sensitivity of P. falciparum field isolates to the antimalarial drug pipeline (2R01AI139179-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10734407. Licensed CC0.

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