Na+-NQR (Na+-translocating NADH:ubiquinone oxidoreductase) as a novel target for antibiotics

Abstract The recent breakthrough in structural studies on Na+-translocating NADH:ubiquinone oxidoreductase (Na+-NQR) from the human pathogen Vibrio cholerae creates a perspective for the systematic design of inhibitors for this unique enzyme, which is the major Na+ pump in aerobic pathogens. Widespr...

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Bibliographic Details
Published in:FEMS microbiology reviews 2017-09, Vol.41 (5), p.653-671
Main Authors: Dibrov, Pavel, Dibrov, Elena, Pierce, Grant N.
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - metabolism
Antibiotics
Antimicrobial agents
Bacteria
Drug Delivery Systems
Drug development
Drug Discovery
Electron Transport Complex I - antagonists & inhibitors
Electron Transport Complex I - metabolism
Energy metabolism
Enzyme Inhibitors - metabolism
Enzymes
Inhibitors
Metabolism
Molecular chains
Na+/K+-exchanging ATPase
NADH
NADH-ubiquinone oxidoreductase
Nicotinamide adenine dinucleotide
Pathogens
Pharmacology
Sodium
Ubiquinone
Ubiquinone oxidoreductase
Vibrio cholerae - enzymology
Virulence
Waterborne diseases
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Summary:Abstract The recent breakthrough in structural studies on Na+-translocating NADH:ubiquinone oxidoreductase (Na+-NQR) from the human pathogen Vibrio cholerae creates a perspective for the systematic design of inhibitors for this unique enzyme, which is the major Na+ pump in aerobic pathogens. Widespread distribution of Na+-NQR among pathogenic species, its key role in energy metabolism, its relation to virulence in different species as well as its absence in eukaryotic cells makes this enzyme especially attractive as a target for prospective antibiotics. In this review, the major biochemical, physiological and, especially, the pharmacological aspects of Na+-NQR are discussed to assess its ‘target potential’ for drug development. A comparison to other primary bacterial Na+ pumps supports the contention that NQR is a first rate prospective target for a new generation of antimicrobials. A new, narrowly targeted furanone inhibitor of NQR designed in our group is presented as a molecular platform for the development of anti-NQR remedies. A comprehensive review of the respiratory sodium pump, Na+-NQR, as a non-traditional antibiotic target including a novel series of Na+-NQR inhibitors recently designed by the authors.
ISSN:1574-6976
0168-6445
1574-6976
DOI:10.1093/femsre/fux032