Inhibitors of Aspartate Transcarbamoylase Inhibit Mycobacterium tuberculosis Growth

Xiaochen Du, Vidhisha Sonawane, Bidong Zhang, Chao Wang, Bram de Ruijter, Alexander S S Dömling*, Norbert Reiling*, Matthew R Groves*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
30 Downloads (Pure)

Abstract

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 MIC 90 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.

Original languageEnglish
Article numbere202300279
Number of pages7
JournalChemMedChem
Volume18
Issue number17
Early online date9-Jun-2023
DOIs
Publication statusPublished - 1-Sept-2023

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