Abstract
Four novel inhibitors of the NorA efflux pump of Staphylococcus aureus, discovered through a virtual screening process, are reported. The four compounds belong to different chemical classes and were tested for their in vitro ability to block the efflux of a well-known NorA substrate, as well as for their ability to potentiate the effect of ciprofloxacin (CPX) on several strains of S. aureus, including a NorA overexpressing strain. Additionally, the MIC values of each of the compounds individually are reported. A structure-activity relationship study was also performed on these novel chemotypes, revealing three new compounds that are also potent NorA inhibitors. The virtual screening procedure employed FLAP, a new methodology based on GRID force field descriptors.
MeSH terms
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology
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Bacterial Proteins / antagonists & inhibitors*
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology
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Ciprofloxacin / pharmacology
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Databases, Factual
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Drug Resistance, Bacterial
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Drug Synergism
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Ethidium / antagonists & inhibitors
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Microbial Sensitivity Tests
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Models, Molecular
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Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
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Phenyl Ethers / chemical synthesis*
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Phenyl Ethers / chemistry
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Phenyl Ethers / pharmacology
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Propanolamines / chemical synthesis*
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Propanolamines / chemistry
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Propanolamines / pharmacology
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Quantitative Structure-Activity Relationship
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Staphylococcus aureus / drug effects*
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Staphylococcus aureus / metabolism
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Benzimidazoles
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Multidrug Resistance-Associated Proteins
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Phenyl Ethers
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Propanolamines
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Sulfonamides
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NorA protein, Staphylococcus
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Ciprofloxacin
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Ethidium