Next generation Glucose-1-phosphate thymidylyltransferase (RmlA) inhibitors: An extended SAR study to direct future design

DOI: 10.1016/j.bmc.2021.116477

Authors: Ganyuan Xiao (University of St Andrews and EaStCHEM) , Magnus S. Alphey (University of St Andrews and EaStCHEM) , Fanny Tran (University of St Andrews and EaStCHEM) , Lisa Pirrie (University of St Andrews and EaStCHEM) , Pierre Milbeo (University of St Andrews and EaStCHEM) , Yi Zhou (University of St Andrews and EaStCHEM) , Jasmine K. Bickel (University of St Andrews and EaStCHEM) , Oxana Kempf (University of St Andrews and EaStCHEM) , Karl Kempf (University of St Andrews and EaStCHEM) , James H. Naismith (University of Oxford; The Rosalind Franklin Institute) , Nicholas J. Westwood (University of St Andrews and EaStCHEM)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry , VOL 12

State: Published (Approved)
Published: October 2021

Abstract: The monosaccharide L-Rhamnose is an important component of bacterial cell walls. The first step in the L-rhamnose biosynthetic pathway is catalysed by glucose-1-phosphate thymidylyltransferase (RmlA), which condenses glucose-1-phosphate (Glu-1-P) with deoxythymidine triphosphate (dTTP) to yield dTDP-D-glucose. In addition to the active site where catalysis of this reaction occurs, RmlA has an allosteric site that is important for its function. Building on previous reports, SAR studies have explored further the allosteric site, leading to the identification of very potent P. aeruginosa RmlA inhibitors. Modification at the C6-NH2 of the inhibitor’s pyrimidinedione core structure was tolerated. X-ray crystallographic analysis of the complexes of P.aeruginosa RmlA with the novel analogues revealed that C6-aminoalkyl substituents can be used to position a modifiable amine just outside the allosteric pocket. This opens up the possibility of linking a siderophore to this class of inhibitor with the goal of enhancing bacterial cell wall permeability.

Journal Keywords: Antibacterial drug discovery; Bacterial cell wall synthesis; RmlA; Structure-based optimization

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 19/10/2021 09:35

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)