Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc1 Inhibition Strategy for Malaria.
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.
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.
Allison M
0000-0002-5006-3611
AM
Stickles
Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, and Emergency Medicine, Oregon Health & Science University, Portland, Oregon, USA.
Martin J
MJ
Smilkstein
Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
Joanne M
JM
Morrisey
VA Medical Center, Portland, Oregon, USA.
Yuexin
Y
Li
VA Medical Center, Portland, Oregon, USA.
Isaac P
IP
Forquer
VA Medical Center, Portland, Oregon, USA.
Jane X
JX
Kelly
VA Medical Center, Portland, Oregon, USA.
Sovitj
S
Pou
VA Medical Center, Portland, Oregon, USA.
Rolf W
RW
Winter
VA Medical Center, Portland, Oregon, USA.
Aaron
A
Nilsen
Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
Akhil B
AB
Vaidya
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.
Michael K
MK
Riscoe
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone / Q000494:pharmacology*; D004338:Drug Combinations; D004359:Drug Therapy, Combination / Q000379:methods; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors*; D005260:Female; D016778:Malaria, Falciparum / Q000188:drug therapy*; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects; D002727:Proguanil / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*
C000601913:6-Chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one; D000962:Antimalarials; D004338:Drug Combinations; D015363:Quinolones; C109496:atovaquone, proguanil drug combination; D014450:Electron Transport Complex III; D002727:Proguanil; D053626:Atovaquone