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Journal article
Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc(1) Inhibition Strategy for Malaria
Antimicrobial agents and chemotherapy, v 60(8), pp 4853-4859
01 Aug 2016
PMID: 27270285
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Antimalarial combination therapies play a crucial role in preventing the emergence of drug-resistant Plasmodium parasites. Although artemisinin-based combination therapies (ACTs) comprise the majority of these formulations, inhibitors of the mitochondrial cytochrome bc(1) complex (cyt bc(1)) are among the few compounds that are effective for both acute antimalarial treatment and prophylaxis. There are two known sites for inhibition within cyt bc(1): atovaquone (ATV) blocks the quinol oxidase (Q(o)) site of cyt bc(1), while some members of the endochin-like quinolone (ELQ) family, including preclinical candidate ELQ-300, inhibit the quinone reductase (Q(i)) site and retain full potency against ATV-resistant Plasmodium falciparum strains with Qo site mutations. Here, we provide the first in vivo comparison of ATV, ELQ-300, and combination therapy consisting of ATV plus ELQ-300 (ATV: ELQ-300), using P. yoelii murine models of malaria. In our monotherapy assessments, we found that ATV functioned as a single-dose curative compound in suppressive tests whereas ELQ-300 demonstrated a unique cumulative dosing effect that successfully blocked recrudescence even in a high-parasitemia acute infection model. ATV: ELQ-300 therapy was highly synergistic, and the combination was curative with a single combined dose of 1 mg/kg of body weight. Compared to the ATV: proguanil (Malarone) formulation, ATV: ELQ-300 was more efficacious in multiday, acute infection models and was equally effective at blocking the emergence of ATV-resistant parasites. Ultimately, our data suggest that dual-site inhibition of cyt bc(1) is a valuable strategy for antimalarial combination therapy and that Q(i) site inhibitors such as ELQ-300 represent valuable partner drugs for the clinically successful Q(o) site inhibitor ATV.
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- Title
- Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc(1) Inhibition Strategy for Malaria
- Creators
- Allison M. Stickles - Oregon Health & Science UniversityMartin J. Smilkstein - Oregon Health & Science UniversityJoanne M. Morrisey - Drexel UniversityYuexin Li - Portland VA Medical CenterIsaac P. Forquer - Portland VA Medical CenterJane X. Kelly - Portland VA Medical CenterSovitj Pou - Portland VA Medical CenterRolf W. Winter - Portland VA Medical CenterAaron Nilsen - Portland VA Medical CenterAkhil B. Vaidya - Drexel UniversityMichael K. Riscoe - Oregon Health & Science University
- Publication Details
- Antimicrobial agents and chemotherapy, v 60(8), pp 4853-4859
- Publisher
- Amer Soc Microbiology
- Number of pages
- 7
- Grant note
- I01BX003312 / Veterans Affairs; US Department of Veterans Affairs 01-BX003312 / United States Department of Veterans Affairs; US Department of Veterans Affairs 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) PR130649 / United States Department of Defense AI100569; AI079182; AI028398 / HHS \ National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000380792600049
- Scopus ID
- 2-s2.0-84979207872
- Other Identifier
- 991019168187904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy