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Inhibition of Cytochrome bc(1) as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy
Journal article   Open access   Peer reviewed

Inhibition of Cytochrome bc(1) as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy

Allison M. Stickles, Li-Min Ting, Joanne M. Morrisey, Yuexin Li, Michael W. Mather, Erin Meermeier, April M. Pershing, Isaac P. Forquer, Galen P. Miley, Sovitj Pou, …
The American journal of tropical medicine and hygiene, v 92(6), pp 1195-1201
01 Jun 2015
PMID: 25918204
url
https://doi.org/10.4269/ajtmh.14-0553View
Published, Version of Record (VoR)Open Access (License Unspecified) Open

Abstract

Life Sciences & Biomedicine Public, Environmental & Occupational Health Science & Technology Tropical Medicine
Single-dose therapies for malaria have been proposed as a way to reduce the cost and increase the effectiveness of antimalarial treatment. However, no compound to date has shown single-dose activity against both the blood-stage Plasmodium parasites that cause disease and the liver-stage parasites that initiate malaria infection. Here, we describe a subset of cytochrome bc(1) (cyt bc(1)) inhibitors, including the novel 4(1H)-quinolone ELQ-400, with single-dose activity against liver, blood, and transmission-stage parasites in mouse models of malaria. Although cyt bc(1) inhibitors are generally classified as slow-onset antimalarials, we found that a single dose of ELQ-400 rapidly induced stasis in blood-stage parasites, which was associated with a rapid reduction in parasitemia in vivo. ELQ-400 also exhibited a low propensity for drug resistance and was active against atovaquone-resistant P. falciparum strains with point mutations in cyt bc(1). Ultimately, ELQ-400 shows that cyt bc(1) inhibitors can function as single-dose, blood-stage antimalarials and is the first compound to provide combined treatment, prophylaxis, and transmission blocking activity for malaria after a single oral administration. This remarkable multi-stage efficacy suggests that metabolic therapies, including cyt bc(1) inhibitors, may be valuable additions to the collection of single-dose antimalarials in current development.

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Collaboration types
Domestic collaboration
Web of Science research areas
Public, Environmental & Occupational Health
Tropical Medicine
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