Inhibitors of Aspartate Transcarbamoylase Inhibit Mycobacterium tuberculosis Growth

Aspartate transcarbamoylase (ATCase) plays a key role in the second step of de novo pyrimidine biosynthesis in eukaryotes and has been proposed to be a target to suppress cell proliferation in E. coli, human cells and the malarial parasite. We hypothesized that a library of ATCase inhibitors develop...

Full description

Saved in:
Bibliographic Details
Published in:ChemMedChem 2023-09, Vol.18 (17), p.e202300279-n/a
Main Authors: Du, Xiaochen, Sonawane, Vidhisha, Zhang, Bidong, Wang, Chao, Ruijter, Bram, Dömling, Alexander S. S., Reiling, Norbert, Groves, Matthew R.
Format: Article
Language:English
Subjects:
allosteric inhibition
Allosteric properties
aspartate transcarbamoylase
Biosynthesis
Cell culture
Cell growth
Cell proliferation
E coli
Eukaryotes
Inhibitors
Malaria
molecular docking
Mycobacterium tuberculosis
Parasites
pyrimidine biosynthesis
Tuberculosis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Aspartate transcarbamoylase (ATCase) plays a key role in the second step of de novo pyrimidine biosynthesis in eukaryotes and has been proposed to be a target to suppress cell proliferation in E. coli, human cells and the malarial parasite. We hypothesized that a library of ATCase inhibitors developed for malarial ATCase (PfATCase) may also contain inhibitors of the tubercular ATCase and provide a similar inhibition of cellular proliferation. Of the 70 compounds screened, 10 showed single‐digit micromolar inhibition in an in vitro activity assay and were tested for their effect on M. tuberculosis cell growth in culture. The most promising compound demonstrated a MIC90 of 4 μM. A model of MtbATCase was generated using the experimental coordinates of PfATCase. In silico docking experiments showed this compound can occupy a similar allosteric pocket on MtbATCase to that seen on PfATCase, explaining the observed species selectivity seen for this compound series. Allosteric inhibitors designed to bind to the malarial aspartate transcarbamoylase (ATCase) and inhibit pyrimidine biosynthesis are shown to also inhibit the ATCase of M. tuberculosis. The most potent of this series also inhibit proliferation of M. tuberculosis in cell culture.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202300279