Abstract
The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.
MeSH terms
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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / metabolism
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Crystallography, X-Ray
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DNA Gyrase / metabolism*
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Gram-Positive Bacteria / drug effects
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Gram-Positive Bacteria / enzymology
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Gram-Positive Bacterial Infections / drug therapy
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Gram-Positive Bacterial Infections / microbiology
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Humans
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Indoles / chemistry
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Indoles / pharmacology*
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Methicillin-Resistant Staphylococcus aureus / drug effects
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Methicillin-Resistant Staphylococcus aureus / enzymology*
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Models, Molecular
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Staphylococcal Infections / drug therapy
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Staphylococcal Infections / microbiology
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Topoisomerase II Inhibitors / chemistry
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Topoisomerase II Inhibitors / pharmacology*
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Urea / analogs & derivatives
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Urea / pharmacology*
Substances
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4-azaindole
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Bacterial Proteins
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Indoles
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Topoisomerase II Inhibitors
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Urea
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DNA Gyrase