2. Academic Validation
  3. Subtle changes in endochin-like quinolone structure alter the site of inhibition within the cytochrome bc1 complex of Plasmodium falciparum

Subtle changes in endochin-like quinolone structure alter the site of inhibition within the cytochrome bc1 complex of Plasmodium falciparum

  • Antimicrob Agents Chemother. 2015 Apr;59(4):1977-82. doi: 10.1128/AAC.04149-14.
Allison M Stickles 1,  Mariana Justino de Almeida 2,  Joanne M Morrisey 3,  Kayla A Sheridan 4,  Isaac P Forquer 4,  Aaron Nilsen 4,  Rolf W Winter 4,  Jeremy N Burrows 5,  David A Fidock 6,  Akhil B Vaidya 3,  Michael K Riscoe 7
Affiliations

Affiliations

  • 1 Departments of Physiology and Pharmacology, Molecular Microbiology, and Immunology, Oregon Health & Science University, Portland, Oregon, USA stickles@ohsu.edu riscoem@ohsu.edu.
  • 2 Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, USA.
  • 3 Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
  • 4 VA Medical Center, Portland, Oregon, USA.
  • 5 Medicines for Malaria Venture, Geneva, Switzerland.
  • 6 Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, USA Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
  • 7 Departments of Physiology and Pharmacology, Molecular Microbiology, and Immunology, Oregon Health & Science University, Portland, Oregon, USA VA Medical Center, Portland, Oregon, USA stickles@ohsu.edu riscoem@ohsu.edu.
PMID: 25605352 DOI: 10.1128/AAC.04149-14
Abstract

The cytochrome bc1 complex (cyt bc1) is the third component of the mitochondrial electron transport chain and is the target of several potent antimalarial compounds, including the naphthoquinone atovaquone (ATV) and the 4(1H)-quinolone ELQ-300. Mechanistically, cyt bc1 facilitates the transfer of electrons from ubiquinol to cytochrome c and contains both oxidative (Qo) and reductive (Qi) catalytic sites that are amenable to small-molecule inhibition. Although many antimalarial compounds, including ATV, effectively target the Qo site, it has been challenging to design selective Qi site inhibitors with the ability to circumvent clinical ATV resistance, and little is known about how chemical structure contributes to site selectivity within cyt bc1. Here, we used the proposed Qi site inhibitor ELQ-300 to generate a drug-resistant Plasmodium falciparum clone containing an I22L mutation at the Qi region of cyt b. Using this D1 clone and the Y268S Qo mutant strain, P. falciparum Tm90-C2B, we created a structure-activity map of Qi versus Qo site selectivity for a series of endochin-like 4(1H)-quinolones (ELQs). We found that Qi site inhibition was associated with compounds containing 6-position halogens or aryl 3-position side chains, while Qo site inhibition was favored by 5,7-dihalogen groups or 7-position substituents. In addition to identifying ELQ-300 as a preferential Qi site inhibitor, our data suggest that the 4(1H)-quinolone scaffold is compatible with binding to either site of cyt bc1 and that minor chemical changes can influence Qo or Qi site inhibition by the ELQs.

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