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Journal article
Inhibition of Cytochrome bc(1) as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy
The American journal of tropical medicine and hygiene, v 92(6), pp 1195-1201
01 Jun 2015
PMID: 25918204
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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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Details
- Title
- Inhibition of Cytochrome bc(1) as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy
- Creators
- Allison M. Stickles - Drexel UniversityLi-Min Ting - Drexel UniversityJoanne M. Morrisey - Drexel UniversityYuexin Li - Drexel UniversityMichael W. Mather - Drexel UniversityErin Meermeier - Drexel UniversityApril M. Pershing - Drexel UniversityIsaac P. Forquer - Drexel UniversityGalen P. Miley - Drexel UniversitySovitj Pou - Drexel UniversityRolf W. Winter - Drexel UniversityDavid J. Hinrichs - Drexel UniversityJane X. Kelly - Drexel UniversityKami Kim - Drexel UniversityAkhil B. Vaidya - Drexel UniversityMichael K. Riscoe - Drexel UniversityAaron Nilsen - Drexel University
- Publication Details
- The American journal of tropical medicine and hygiene, v 92(6), pp 1195-1201
- Publisher
- Amer Soc Trop Med & Hygiene
- Number of pages
- 7
- Grant note
- S10RR027308 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA United States Department of Veterans Affairs; US Department of Veterans Affairs I01BX003312 / Veterans Affairs; US Department of Veterans Affairs Stanley Medical Research Institute PR130649 / US DOD PRMRP R01AI028398 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) AI100569; AI079182; AI028398 / NIH NIAID; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) S10RR027308 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) T32GM071338 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000355785400019
- Scopus ID
- 2-s2.0-84930607170
- Other Identifier
- 991019169665104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Public, Environmental & Occupational Health
- Tropical Medicine