Inhibition of cytochrome bc1 as a strategy for single-dose, multi-stage antimalarial therapy

Allison M. Stickles, Li Min Ting, Joanne M. Morrisey, Yuexin Li, Michael W. Mather, Erin Meermeier, April M. Pershing, Isaac P. Forquer, Galen P. Miley, Sovitj Pou, Rolf W. Winter, David J. Hinrichs, Jane X. Kelly, Kami Kim, Akhil B. Vaidya, Michael K. Riscoe, Aaron Nilsen

Research output: Contribution to journalArticle

22 Scopus citations

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 bloodstage Plasmodium parasites that cause disease and the liver-stage parasites that initiate malaria infection. Here, we describe a subset of cytochrome bc1 (cyt bc1) 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 bc1 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 bc1. Ultimately, ELQ-400 shows that cyt bc1 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 bc1 inhibitors, may be valuable additions to the collection of single-dose antimalarials in current development.

Original languageEnglish (US)
Pages (from-to)1195-1201
Number of pages7
JournalAmerican Journal of Tropical Medicine and Hygiene
Volume92
Issue number6
DOIs
StatePublished - Jun 1 2015

ASJC Scopus subject areas

  • Parasitology
  • Virology
  • Infectious Diseases

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    Stickles, A. M., Ting, L. M., Morrisey, J. M., Li, Y., Mather, M. W., Meermeier, E., Pershing, A. M., Forquer, I. P., Miley, G. P., Pou, S., Winter, R. W., Hinrichs, D. J., Kelly, J. X., Kim, K., Vaidya, A. B., Riscoe, M. K., & Nilsen, A. (2015). Inhibition of cytochrome bc1 as a strategy for single-dose, multi-stage antimalarial therapy. American Journal of Tropical Medicine and Hygiene, 92(6), 1195-1201. https://doi.org/10.4269/ajtmh.14-0553