Thiolactomycin-based β-Ketoacyl-AcpM Synthase A (KasA) Inhibitors

Abstract

Background: Potent inhibitors of the tuberculosis drug target KasA are needed. Results: Three-position analogs of the natural product thiolactomycin (TLM) were designed based on transient one-dimensional NOEs that reveal the relative orientation of TLM and a pantetheine analog bound simultaneously to KasA. Conclusion: Three-position analogs of TLM bind to KasA with increased potency. Significance: Optimization of TLM will lead to improved inhibitors of KasA.

New Approaches to Target the Mycolic Acid Biosynthesis Pathway for the Development of Tuberculosis Therapeutics

“…Validated chemotypes may now be rapidly advanced using target-based optimization including structure based drug design which takes advantage of the rapidly increasing numbers of M. tb crystal structures available. These structures also open the door to other discovery techniques which are showing great promise including fragment-based drug design techniques as has already been applied to the discovery of novel antigen 85C inhibitors [76]. Fragment-based drug design has many advantages over traditional HTS approaches, including a much better coverage of chemical space which is compressed at lower molecular weights, considerably increasing the random statistical chance of finding true binders.…”

“…Substitutions included alkyl, branched alkyl, unsaturated alkyl and aromatic groups and they found that the isoprenyl group was required for activity [74]. To help further the SAR, Kapilashrami et al modified the alkyl group at the 3-position [76]. Substitutions included alkyl, acyl and aromatic functional groups [76].…”

“…To help further the SAR, Kapilashrami et al modified the alkyl group at the 3-position [76]. Substitutions included alkyl, acyl and aromatic functional groups [76]. They were able to increase the K i by approximately 2- and 3-fold against the C171Q mutant designed to mimic the acylated enzyme intermediate form [77, 78].…”

“…They were able to increase the K i by approximately 2- and 3-fold against the C171Q mutant designed to mimic the acylated enzyme intermediate form [77, 78]. The K i values for TLM ( 21 ), acetyl- ( 22 ) and trifluoroacetyl-TLM ( 23 ) are approximately 175, 8 and 12 respectively [76]. Despite promising inhibitory activity against the enzyme, TLM has modest whole cell growth inhibition, with an antitubercular MIC value of approximately 62.5 μM [73, 74].…”

A Structural Basis for Biguanide Activity

“…The 2D spectra often produced weak ILOE cross-peaks with interference from F1 apodization noise due to intense methyl resonance from metformin and some of the other ligands at the high concentrations (~5 mM) used in these studies. Improved signal-to-noise and artifact free spectra were obtained using 1D ILOE experiments 55 obtained using an Agilent 800 MHz NMR spectrometer equipped with a cryogenic triple resonance probe. The 1D ILOE experiments were carried out using the ChemPack (Agilent Inc, Santa Clara CA) NOESY1D experiment.…”