Targeting the cytochrome bc1 complex of Leishmania parasites for discovery of novel drugs

Diana Ortiz, Isaac Forquer, Jan Boitz, Radika Soysa, Carolyn Elya, Audrey Fulwiler, Aaron Nilsen, Tamsen Polley, Michael Riscoe, Buddy Ullman, Scott Landfear

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Endochin-like quinolones (ELQs) are potent and specific inhibitors of cytochrome bc1 from Plasmodium falciparum and Toxoplasma gondii and show promise for novel antiparasitic drug development. To determine whether the mitochondrial electron transport chain of Leishmania parasites could be targeted similarly for drug development, we investigated the activity of 134 structurally diverse ELQs. A cohort of ELQs was selectively toxic to amastigotes of Leishmania mexicana and L. donovani, with 50% inhibitory concentrations (IC50s) in the low micromolar range, but the structurally similar hydroxynaphthoquinone buparvaquone was by far the most potent inhibitor of electron transport, ATP production, and intracellular amastigote growth. Cytochrome bc1 is thus a promising target for novel antileishmanial drugs, and further improvements on the buparvaquone scaffold are warranted for development of enhanced therapeutics.

Original languageEnglish (US)
Pages (from-to)4972-4982
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

Electron Transport Complex III
Leishmania
Quinolones
Drug Discovery
Parasites
Electron Transport
Leishmania mexicana
Antiparasitic Agents
Food Chain
Poisons
Toxoplasma
Plasmodium falciparum
Pharmaceutical Preparations
Inhibitory Concentration 50
Adenosine Triphosphate
Growth
buparvaquone
Therapeutics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Targeting the cytochrome bc1 complex of Leishmania parasites for discovery of novel drugs. / Ortiz, Diana; Forquer, Isaac; Boitz, Jan; Soysa, Radika; Elya, Carolyn; Fulwiler, Audrey; Nilsen, Aaron; Polley, Tamsen; Riscoe, Michael; Ullman, Buddy; Landfear, Scott.

In: Antimicrobial Agents and Chemotherapy, Vol. 60, No. 8, 01.08.2016, p. 4972-4982.

Research output: Contribution to journalArticle

Ortiz, Diana ; Forquer, Isaac ; Boitz, Jan ; Soysa, Radika ; Elya, Carolyn ; Fulwiler, Audrey ; Nilsen, Aaron ; Polley, Tamsen ; Riscoe, Michael ; Ullman, Buddy ; Landfear, Scott. / Targeting the cytochrome bc1 complex of Leishmania parasites for discovery of novel drugs. In: Antimicrobial Agents and Chemotherapy. 2016 ; Vol. 60, No. 8. pp. 4972-4982.
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AU - Fulwiler, Audrey

AU - Nilsen, Aaron

AU - Polley, Tamsen

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