Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc1 Inhibition Strategy for Malaria.

Autor:	Stickles AM; Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, and Emergency Medicine, Oregon Health & Science University, Portland, Oregon, USA stickles@ohsu.edu riscoem@ohsu.edu., Smilkstein MJ; Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, and Emergency Medicine, Oregon Health & Science University, Portland, Oregon, USA., Morrisey JM; Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA., Li Y; VA Medical Center, Portland, Oregon, USA., Forquer IP; VA Medical Center, Portland, Oregon, USA., Kelly JX; VA Medical Center, Portland, Oregon, USA., Pou S; VA Medical Center, Portland, Oregon, USA., Winter RW; VA Medical Center, Portland, Oregon, USA., Nilsen A; VA Medical Center, Portland, Oregon, USA., Vaidya AB; Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA., Riscoe MK; Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, and Emergency Medicine, Oregon Health & Science University, Portland, Oregon, USA VA Medical Center, Portland, Oregon, USA stickles@ohsu.edu riscoem@ohsu.edu.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2016 Jul 22; Vol. 60 (8), pp. 4853-9. Date of Electronic Publication: 2016 Jul 22 (Print Publication: 2016).
DOI:	10.1128/AAC.00791-16
Abstrakt:	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 bc1 complex (cyt bc1) are among the few compounds that are effective for both acute antimalarial treatment and prophylaxis. There are two known sites for inhibition within cyt bc1: atovaquone (ATV) blocks the quinol oxidase (Qo) site of cyt bc1, while some members of the endochin-like quinolone (ELQ) family, including preclinical candidate ELQ-300, inhibit the quinone reductase (Qi) 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 bc1 is a valuable strategy for antimalarial combination therapy and that Qi site inhibitors such as ELQ-300 represent valuable partner drugs for the clinically successful Qo site inhibitor ATV. (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
Databáze:	MEDLINE
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