Journal article
Resistance mutations reveal the atovaquone‐binding domain of cytochrome b in malaria parasites
Molecular microbiology, v 33(4), pp 704-711
Aug 1999
PMID: 10447880
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Atovaquone represents a class of antimicrobial agents with a broad‐spectrum activity against various parasitic infections, including malaria, toxoplasmosis and Pneumocystis pneumonia. In malaria parasites, atovaquone inhibits mitochondrial electron transport at the level of the cytochrome bc1 complex and collapses mitochondrial membrane potential. In addition, this drug is unique in being selectively toxic to parasite mitochondria without affecting the host mitochondrial functions. A better understanding of the structural basis for the selective toxicity of atovaquone could help in designing drugs against infections caused by mitochondria‐containing parasites. To that end, we derived nine independent atovaquone‐resistant malaria parasite lines by suboptimal treatment of mice infected with Plasmodium yoelii; these mutants exhibited resistance to atovaquone‐mediated collapse of mitochondrial membrane potential as well as inhibition of electron transport. The mutants were also resistant to the synergistic effects of atovaquone/ proguanil combination. Sequencing of the mitochondrially encoded cytochrome b gene placed these mutants into four categories, three with single amino acid changes and one with two adjacent amino acid changes. Of the 12 nucleotide changes seen in the nine independently derived mutants 11 replaced A:T basepairs with G:C basepairs, possibly because of reactive oxygen species resulting from atovaquone treatment. Visualization of the resistance‐conferring amino acid positions on the recently solved crystal structure of the vertebrate cytochrome bc1 complex revealed a discrete cavity in which subtle variations in hydrophobicity and volume of the amino acid side‐chains may determine atovaquone‐binding affinity, and thereby selective toxicity. These structural insights may prove useful in designing agents that selectively affect cytochrome bc1 functions in a wide range of eukaryotic pathogens.
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Details
- Title
- Resistance mutations reveal the atovaquone‐binding domain of cytochrome b in malaria parasites
- Creators
- Indresh K SrivastavaJoanne M MorriseyElisabeth DarrouzetFevzi DaldalAkhil B Vaidya
- Publication Details
- Molecular microbiology, v 33(4), pp 704-711
- Publisher
- Blackwell Science Ltd; Oxford BSL
- Number of pages
- 8
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000082478000004
- Scopus ID
- 2-s2.0-0032781364
- Other Identifier
- 991014878470004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Microbiology