Dissertation

Discovery of novel antibiotics targets in bacterial priority pathogens

Antimicrobial resistance is one of the biggest threats to human health worldwide in the coming decennia.

Author: J.P.V. Pols
Date: 04 March 2026
Links: Thesis in Leiden Repository

While resistant bacteria are on the rise, no new antibiotic classes have passed clinical trials since the 1980s. Additionally, covalent inhibitors that bind irreversibly with their protein targets are underrepresented in drugs; with careful screening, these structures possess many advantages over conventional drugs. This thesis aimed to discover protein targets that are essential for bacterial survival, with the application of covalent irreversible inhibitors, for the discovery of novel antibiotics. A library of 10,000 compounds was tested for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), Neisseria gonorrhoeae, and Mycobacterium tuberculosis. Selections of compounds with antibacterial activity were then used to elucidate their protein targets. For the different bacteria, different choices and different follow-up experiments, from validations to structure-activity relationship studies, were performed. For each bacterium, compounds with antibacterial activity were identified as well as essential protein targets. This research has expanded on the field of antibiotic research with a clear workflow and numerous starting points for the development of covalent inhibitors as antibiotics for pathogenic bacteria.