1. In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas.
- Author
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Ottavi S, Scarry SM, Mosior J, Ling Y, Roberts J, Singh A, Zhang D, Goullieux L, Roubert C, Bacqué E, Lagiakos HR, Vendome J, Moraca F, Li K, Perkowski AJ, Ramesh R, Bowler MM, Tracy W, Feher VA, Sacchettini JC, Gold BS, Nathan CF, and Aubé J
- Subjects
- Bacterial Proteins antagonists & inhibitors, Binding Sites, Crystallography, X-Ray, Guanidine chemistry, Guanidine metabolism, Guanidine pharmacology, Kinetics, Microbial Sensitivity Tests, Molecular Conformation, Molecular Dynamics Simulation, Mycobacterium tuberculosis drug effects, Structure-Activity Relationship, Transferases (Other Substituted Phosphate Groups) antagonists & inhibitors, Urea chemistry, Urea metabolism, Urea pharmacology, Bacterial Proteins metabolism, Guanidine analogs & derivatives, Mycobacterium tuberculosis enzymology, Transferases (Other Substituted Phosphate Groups) metabolism, Urea analogs & derivatives
- Abstract
A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis . The structure-activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 ( 1 ), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including 1 , have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Ca
v 1.2 and Nav 1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as 5k ( p -benzamide) and 5n ( p -phenylsulfonamide).- Published
- 2022
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