Abstract
4'-Phosphopantetheinyl transferases (PPTases) catalyze a post-translational modification essential to bacterial cell viability and virulence. We present the discovery and medicinal chemistry optimization of 2-pyridinyl-N-(4-aryl)piperazine-1-carbothioamides, which exhibit submicromolar inhibition of bacterial Sfp-PPTase with no activity toward the human orthologue. Moreover, compounds within this class possess antibacterial activity in the absence of a rapid cytotoxic response in human cells. An advanced analogue of this series, ML267 (55), was found to attenuate production of an Sfp-PPTase-dependent metabolite when applied to Bacillus subtilis at sublethal doses. Additional testing revealed antibacterial activity against methicillin-resistant Staphylococcus aureus , and chemical genetic studies implicated efflux as a mechanism for resistance in Escherichia coli . Additionally, we highlight the in vitro absorption, distribution, metabolism, and excretion and in vivo pharmacokinetic profiles of compound 55 to further demonstrate the potential utility of this small-molecule inhibitor.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / pharmacokinetics
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Anti-Bacterial Agents / pharmacology
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Bacterial Proteins / antagonists & inhibitors*
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Dipeptides / pharmacology
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Drug Resistance, Bacterial
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Drug Synergism
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Escherichia coli / drug effects
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Escherichia coli / metabolism
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Gram-Positive Bacteria / drug effects
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Gram-Positive Bacteria / metabolism
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Humans
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Male
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Mice
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Microbial Sensitivity Tests
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Microsomes, Liver / metabolism
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Secondary Metabolism
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Structure-Activity Relationship
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Thiourea / analogs & derivatives*
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Thiourea / chemical synthesis
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Thiourea / pharmacokinetics
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Thiourea / pharmacology
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Transferases (Other Substituted Phosphate Groups) / antagonists & inhibitors*
Substances
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4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide
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Anti-Bacterial Agents
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Bacterial Proteins
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Dipeptides
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Pyridines
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phenylalanine arginine beta-naphthylamide
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phosphopantetheinyl transferase
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Transferases (Other Substituted Phosphate Groups)
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Thiourea