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Journal article
Subtle Changes in Endochin-Like Quinolone Structure Alter the Site of Inhibition within the Cytochrome bc(1) Complex of Plasmodium falciparum
Antimicrobial agents and chemotherapy, v 59(4), pp 1977-1982
01 Apr 2015
PMID: 25605352
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Abstract
The cytochrome bc(1) complex (cyt bc(1)) 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 bc(1) facilitates the transfer of electrons from ubiquinol to cytochrome c and contains both oxidative (Q(o)) and reductive (Q(i)) catalytic sites that are amenable to small-molecule inhibition. Although many antimalarial compounds, including ATV, effectively target the Q(o) site, it has been challenging to design selective Q(i) site inhibitors with the ability to circumvent clinical ATV resistance, and little is known about how chemical structure contributes to site selectivity within cyt bc(1). Here, we used the proposed Q(i) site inhibitor ELQ-300 to generate a drug-resistant Plasmodium falciparum clone containing an I22L mutation at the Q(i) region of cyt b. Using this D1 clone and the Y268S Q(o) mutant strain, P. falciparum Tm90-C2B, we created a structure-activity map of Q(i) versus Q(o) site selectivity for a series of endochin-like 4(1H)-quinolones (ELQs). We found that Q(i) site inhibition was associated with compounds containing 6-position halogens or aryl 3-position side chains, while Q(o) site inhibition was favored by 5,7-dihalogen groups or 7-position substituents. In addition to identifying ELQ-300 as a preferential Q(i) site inhibitor, our data suggest that the 4(1H)-quinolone scaffold is compatible with binding to either site of cyt bc(1) and that minor chemical changes can influence Q(o) or Q(i) site inhibition by the ELQs.
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Details
- Title
- Subtle Changes in Endochin-Like Quinolone Structure Alter the Site of Inhibition within the Cytochrome bc(1) Complex of Plasmodium falciparum
- Creators
- Allison M. Stickles - Oregon Health & Science UniversityMariana Justino de Almeida - Columbia University Medical CenterJoanne M. Morrisey - Drexel UniversityKayla A. Sheridan - Portland VA Medical CenterIsaac P. Forquer - Portland VA Medical CenterAaron Nilsen - Portland VA Medical CenterRolf W. Winter - Portland VA Medical CenterJeremy N. Burrows - Medicines for Malaria VentureDavid A. Fidock - Columbia University Medical CenterAkhil B. Vaidya - Drexel UniversityMichael K. Riscoe - Oregon Health & Science University
- Publication Details
- Antimicrobial agents and chemotherapy, v 59(4), pp 1977-1982
- Publisher
- Amer Soc Microbiology
- Number of pages
- 6
- Grant note
- U.S. Department of Veterans Affairs; US Department of Veterans Affairs R01AI100569 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) I01BX003312 / Veterans Affairs; US Department of Veterans Affairs Stanley Medical Research Institute AI079182; AI100569; AI028398 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Medicines for Malaria Venture (Geneva, Switzerland) T32GM071338 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000354993700020
- Scopus ID
- 2-s2.0-84928901533
- Other Identifier
- 991019168779804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy