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.
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.
National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Timothy L
TL
Foley
Ganesha
G
Rai
Adam
A
Yasgar
Thomas
T
Daniel
Heather L
HL
Baker
Matias
M
Attene-Ramos
Nicolas M
NM
Kosa
William
W
Leister
Michael D
MD
Burkart
Ajit
A
Jadhav
Anton
A
Simeonov
David J
DJ
Maloney
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D064210:Secondary Metabolism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors*
C587731:4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004151:Dipeptides; D011725:Pyridines; C419365:phenylalanine arginine beta-naphthylamide; C082662:phosphopantetheinyl transferase; D017855:Transferases (Other Substituted Phosphate Groups); D013890:Thiourea