Abstract
New classes of antibiotics are urgently needed to counter increasing levels of pathogen resistance. Peptide deformylase (PDF) was originally selected as a specific bacterial target, but a human homologue, the inhibition of which causes cell death, was recently discovered. We developed a dual-screening strategy for selecting highly effective compounds with low inhibition effect against human PDF. We selected a new scaffold in vitro that discriminated between human and bacterial PDFs. Analyses of structure-activity relationships identified potent antibiotics such as 2-(5-bromo-1H-indol-3-yl)-N-hydroxyacetamide (6b) with the same mode of action in vivo as previously identified PDF inhibitors but without the apoptotic effects of these inhibitors in human cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amidohydrolases / antagonists & inhibitors*
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Amidohydrolases / chemistry
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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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Apoptosis / drug effects
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Bacillus subtilis / drug effects
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Escherichia coli / drug effects
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Escherichia coli / enzymology
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Geobacillus stearothermophilus / enzymology
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Humans
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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KB Cells
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Magnetic Resonance Spectroscopy
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Microbial Sensitivity Tests
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Models, Molecular
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Structure-Activity Relationship
Substances
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2-(5-bromo-1H-indol-3-yl)-N-hydroxyacetamide
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Anti-Bacterial Agents
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Hydroxamic Acids
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Indoles
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Amidohydrolases
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peptide deformylase