4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide (ML267), a potent inhibitor of bacterial phosphopantetheinyl transferase that attenuates secondary metabolism and thwarts bacterial growth.

Medicinal Chemistry


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.


Foley, Timothy L; Rai Bantukallu, Ganesha; Yasgar, Adam; Daniel, Thomas; Baker, Heather; Attene-Ramos, Matias; Kosa, Nicolas M; Leister, William; Burkart, Michael D; Jadhav, Ajit; Simeonov, Anton; Maloney, David J;


  • Animals
  • Anti-Bacterial Agents/ chemical synthesis
  • Anti-Bacterial Agents/ pharmacokinetics
  • Anti-Bacterial Agents/ pharmacology
  • Bacterial Proteins/ antagonists & inhibitors
  • Dipeptides/ pharmacology
  • Drug Resistance, Bacterial
  • Drug Synergism
  • Escherichia coli/ drug effects
  • Escherichia coli/ metabolism
  • Gram-Positive Bacteria/ drug effects
  • Gram-Positive Bacteria/ metabolism
  • Humans
  • Male
  • Mice
  • Microbial Sensitivity Tests
  • Microsomes, Liver/ metabolism
  • Pyridines/ chemical synthesis
  • Pyridines/ pharmacokinetics
  • Pyridines/ pharmacology
  • Secondary Metabolism
  • Structure-Activity Relationship
  • Thiourea/ analogs & derivatives
  • Thiourea/ chemical synthesis
  • Thiourea/ pharmacokinetics
  • Thiourea/ pharmacology
  • Transferases (Other Substituted Phosphate Groups)/ antagonists & inhibitors

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