ArticleAntimicrobial agents and chemotherapy2016
Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc1 Inhibition Strategy for Malaria.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 60 citations in OpenAlex.
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- Synthesis of Deuterated Endochin-Like Quinolones.Journal of labelled compounds & radiopharmaceuticals · 2024Article
- Mitochondrial CytochromeTropical medicine and infectious disease · 2024Review
- Atovaquone inhibits colorectal cancer metastasis by regulating PDGFRβ/NF-κB signaling pathway.BMC cancer · 2023Article
- Antimalarial drug discovery: progress and approaches.Nature reviews. Drug discovery · 2023Review
- Unique Properties of Apicomplexan Mitochondria.Annual review of microbiology · 2023Review
- Structure-activity relationships ofExpert opinion on drug discovery · 2022Article
- Siccanin Is a Dual-Target Inhibitor ofPharmaceuticals (Basel, Switzerland) · 2022Article
- Metabolic changes accompanying the loss of fumarate hydratase and malate-quinone oxidoreductase in the asexual blood stage of Plasmodium falciparum.The Journal of biological chemistry · 2022Article
- Dual inhibition of theFrontiers in veterinary science · 2022Article
- Bloom Helicase Along with Recombinase Rad51 Repairs the Mitochondrial Genome of the Malaria Parasite.mSphere · 2021Article
- Endochin-like quinolones (ELQs) and bumped kinase inhibitors (BKIs): Synergistic and additive effects of combined treatments against Neospora caninum infection in vitro and in vivo.International journal for parasitology. Drugs and drug resistance · 2021Article
- Assessment of the Activity of Decoquinate and Its Quinoline-Molecules (Basel, Switzerland) · 2021Article
- Design, synthesis, and biological evaluation of multiple targeting antimalarials.Acta pharmaceutica Sinica. B · 2021Article
- Treatment of Human Babesiosis: Then and Now.Pathogens (Basel, Switzerland) · 2021Review
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11 authors at 3 institutions in 1 country.
Funding
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 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.
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