Hit-optimization using target-directed dynamic combinatorial chemistry: development of inhibitors of the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase

Abstract

Target-directed dynamic combinatorial chemistry (tdDCC) enables identification, as well as optimization of ligands for un(der)explored targets such as the anti-infective target 1-deoxy-D-xylulose-5-phosphate synthase (DXPS). We report the use of tdDCC...

First crystal structures of 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization

“…In this report, we describe the application of our truncation strategy on the DXPS homologue of M. tuberculosis , as a representative pathogen in the focus of several drug-design projects 30 . Following the truncation approach, we were able to obtain protein crystals and report herein the first pathogenic DXPS structures: a holo structure with bound ThDP and a structure containing the enamine reaction intermediate (Fig.…”

Thiamine analogues as inhibitors of pyruvate dehydrogenase and discovery of a thiamine analogue with non-thiamine related antiplasmodial activity

“…6 With the knowledge that TPP-dependent enzymes play a key role in metabolism, several small-molecule inhibitors that demonstrate antimicrobial activities have recently been reported. For example, He and coworkers developed several pyruvate dehydrogenase complex (PDHc) inhibitors for targeting cyanobacteria, 7–9 and the groups of Freel Meyers 10 and Hirsch 11 independently developed inhibitors of 1-deoxy- d -xylulose 5-phosphate synthase (DXPS) from E. coli and Deinococcus radiodurans .…”

High Plasticity of the Amicetin Biosynthetic Pathway in Streptomyces sp. SHP 22-7 Led to the Discovery of Streptcytosine P and Cytosaminomycins F and G and Facilitated the Production of 12F-Plicacetin

“…Supernatants were discarded, and bacteria were thoroughly resuspended in 7H9 medium (10% OADC) in the absence of glycerol and Tween80 by use of a syringe and a 26-gauge syringe needle. Compounds were tested in triplicates (2 × 10 5 bacteria, volume 100 μL) for their antitubercular activity in 2-fold serial dilutions starting from 64 μM using 96-well flat clear-bottom black polystyrene microplates (Corning CellBIND, New York, USA) as recently described . Bacterial growth was measured as relative light units (RLU) from the fluorescence intensity obtained at an excitation wavelength of 575 nm and an emission wavelength of 635 nm (Synergy 2, BioTek Instruments, VT, USA) after 7 days of culture at 37 °C.…”