Periodic Reporting for period 1 - Mtb CoaBC (CoaBC from the Coenzyme A pathway of Mycobacterium tuberculosis as an antimicrobial drug target)
Reporting period: 2018-04-19 to 2020-04-18
I have also been involved in the development and testing of other series of MtbCoaBC inhibitors. Some are thought to bind to a cryptic allosteric site in the CoaB subunit of MtbCoaBC in the course of a study that was recently published in Nature Communications (https://doi.org/10.1038/s41467-020-20224-x). Other compounds were found to have modest activity on whole-cell Mtb, providing a first indication for the putative druggability of CoaBC in Mtb. This study was recently published in ACS Infectious Diseases (https://doi.org/10.1021/acsinfecdis.0c00904). More broadly, we have developed inhibitors of E. coli CoaBC and demonstrated that native mass spectrometry can be used as a screening tool to identify novel inhibitors of this enzyme. This work was recently published in the Biochemical Journal (https://doi.org/10.1042/BCJ20190318).
Moreover, the developed compounds represent an interesting lead series for further development towards antitubercular drugs with a new mechanism of action, thus possessing the potential to target emerging resistant Mtb strains. Antimicrobial resistance is a major public health challenge, and with the rise of drug-resistant mycobacteria, innovative solutions that could lead to the potential development of a pre-clinical candidate active against resistant Mtb are extremely precious. Clearly, knowledge generated during the course of this project has the potential to broadly benefit society.