Application of Fragment‐Based Drug Discovery against DNA Gyrase B

Abstract

Bacterial resistance to antibiotics remains a serious threat to global health. The gyrase B enzyme is a well‐validated target for developing antibacterial drugs. Despite being an attractive target for antibiotic development, there are currently no gyrase B inhibitory drugs on the market. A fragment screen using 1,800 compounds identified 14 fragments that bind to Escherichia coli (E. coli) gyrase B. The detailed characterization of binding is described for all 14 fragments. With the aid of X‐ray crystallography, modifications on a low‐affinity fragment (KD=253 μM, IC50=634 μM) has led to the development of a new class of potent phenyl aminopyrazole inhibitors against E. coli gyrase B (IC50=160 nM). The study presented here combines the use of a set of biophysical techniques including differential scanning fluorimetry, nuclear magnetic resonance, isothermal titration calorimetry, and X‐ray crystallography to methodically identify, quantify, and optimize fragments into new chemical leads.

In Situ Generated Magnesium Cyanide as an Efficient Reagent for Nucleophilic Cyanation of Nitrosoalkenes and Parent Nitronates

“…Also, we developed β‐cyanation of O ‐silyl nitronates Si ‐ 1 through their transformation to N , N ‐bis(silyloxy)enamines 4 and addition of TMSCN via the intermediacy of nitrosoalkenes NSA (Scheme ) . Upon deprotection, cyanooxime derivatives 5 cyclized into valuable 5‐aminoisoxazoles 6 . However, these silicon‐mediated processes have drawbacks associated with the lack of efficiency and the need for desilylation, which is not selective in the case of nitrosoacetals 2 , .…”

Escherichia coli Topoisomerase IV E Subunit and an Inhibitor Binding Mode Revealed by NMR Spectroscopy

“…Inhibitor 2 Can Stabilize eParE-In addition to SPR, thermal shift assays were also used to characterize ligand binding against eParE (9). As shown in Fig.…”

“…Past work done in the group has focused on using fragment-based approaches to develop inhibitors against GyrB (9). Further fragment-based approaches have also developed pyridylurea chemical leads against GyrB/ParE from both Gram-positive and Gram-negative bacteria (10).…”

Application of Fragment-Based Drug Discovery to Versatile Targets

“…This figure illustrated the modification of the compound (Chen et al, 2015). Details should be referred to the original publication (Chen et al, 2015).…”