Inhibitors of Aspartate Transcarbamoylase Inhibit Mycobacterium tuberculosis Growth

• DOI: 10.1002/cmdc.202300279
• Publication Date: 2023-06-09T12:35:02Z
• Authors: Xiaochen Du; Vidhisha Sonawane; Bidong Zhang; Chao Wang; Bram de Ruijter; Alexander S. S. D...; Norbert Reiling; Matthew R. Groves
• Keywords: Aspartate carbamoyltransferase; Pyrimidine metabolism

Aspartate transcarbamoylase (ATCase) plays a key role in the second step of de novo pyrimidine biosynthesis eukaryotes and has been proposed to be target suppress cell proliferation E. coli, human cells malarial parasite. We hypothesized that library ATCase inhibitors developed for (PfATCase) may also contain tubercular provide similar inhibition cellular proliferation. Of 70 compounds screened, 10 showed single-digit micromolar an vitro activity assay were tested their effect on M. tuberculosis growth culture. The most promising compound demonstrated MIC90 4 μM. A model MtbATCase was generated using experimental coordinates PfATCase. In silico docking experiments this can occupy allosteric pocket seen PfATCase, explaining observed species selectivity series.