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*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

2 Citaten (Scopus)
23 Downloads (Pure)

Samenvatting

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.

Originele taal-2English
Artikelnummere202300279
Aantal pagina's7
TijdschriftChemMedChem
Volume18
Nummer van het tijdschrift17
Vroegere onlinedatum9-jun.-2023
DOI's
StatusPublished - 1-sep.-2023

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