Inhibition of cytochrome bc<inf>1</inf> 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

18 Citations (Scopus)

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 bc<inf>1</inf> (cyt bc<inf>1</inf>) 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 bc<inf>1</inf> 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 bc<inf>1</inf>. Ultimately, ELQ-400 shows that cyt bc<inf>1</inf> 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 bc<inf>1</inf> 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

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Electron Transport Complex III
Antimalarials
Malaria
Parasites
Atovaquone
4-Quinolones
Therapeutics
Plasmodium
Parasitemia
Point Mutation
Drug Resistance
Cost-Benefit Analysis
Oral Administration
Liver Diseases
ELQ-400
Liver
Infection

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases
  • Virology

Cite this

Stickles, A. M., Ting, L. M., Morrisey, J. M., Li, Y., Mather, M. W., Meermeier, E., ... Nilsen, A. (2015). Inhibition of cytochrome bc<inf>1</inf> 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

Inhibition of cytochrome bc<inf>1</inf> as a strategy for single-dose, multi-stage antimalarial therapy. / Stickles, Allison M.; Ting, Li Min; Morrisey, Joanne M.; Li, Yuexin; Mather, Michael W.; Meermeier, Erin; Pershing, April M.; Forquer, Isaac P.; Miley, Galen P.; Pou, Sovitj; Winter, Rolf W.; Hinrichs, David J.; Kelly, Jane X.; Kim, Kami; Vaidya, Akhil B.; Riscoe, Michael K.; Nilsen, Aaron.

In: American Journal of Tropical Medicine and Hygiene, Vol. 92, No. 6, 01.06.2015, p. 1195-1201.

Research output: Contribution to journalArticle

Stickles, AM, Ting, LM, Morrisey, JM, Li, Y, Mather, MW, Meermeier, E, Pershing, AM, Forquer, IP, Miley, GP, Pou, S, Winter, RW, Hinrichs, DJ, Kelly, JX, Kim, K, Vaidya, AB, Riscoe, MK & Nilsen, A 2015, 'Inhibition of cytochrome bc<inf>1</inf> as a strategy for single-dose, multi-stage antimalarial therapy', American Journal of Tropical Medicine and Hygiene, vol. 92, no. 6, pp. 1195-1201. https://doi.org/10.4269/ajtmh.14-0553
Stickles, Allison M. ; Ting, Li Min ; Morrisey, Joanne M. ; Li, Yuexin ; Mather, Michael W. ; Meermeier, Erin ; Pershing, April M. ; Forquer, Isaac P. ; Miley, Galen P. ; Pou, Sovitj ; Winter, Rolf W. ; Hinrichs, David J. ; Kelly, Jane X. ; Kim, Kami ; Vaidya, Akhil B. ; Riscoe, Michael K. ; Nilsen, Aaron. / Inhibition of cytochrome bc<inf>1</inf> as a strategy for single-dose, multi-stage antimalarial therapy. In: American Journal of Tropical Medicine and Hygiene. 2015 ; Vol. 92, No. 6. pp. 1195-1201.
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