Date

Monday 09 Feb 2026

Time

15:15 - 15:45

Location

BW019

Supervisor

Stephan Hacker

2nd reviewer

Tom van der Wel

Jury

Bobby Florea

Antimicrobial resistance is one of the significant challenges humanity faces in the 21st century. To combat this resistance development, drugs with novel mechanisms-of-action need to be developed. In this study, a lysine-targeting ethynylbenzaldehyde-based inhibitor was optimized against two high-priority pathogens, MRSA and N. gonorrhoeae, using the Topliss Batchwise Scheme. Nine analogues were synthesized and tested, which enabled the identification of more potent inhibitors and the development of structure-activity relationships for both bacteria. The scheme successfully guided synthesis of a significantly more potent analogue for MRSA, while only a small increase was observed for N. gonorrhoeae. A hemolysis assay indicated that the inhibitor scaffold does not exhibit hemolytic activity in red blood cells. Finally, isoDTB-ABPP identified three potential targets in MRSA: MurG, FemB and TagA. These targets could be inhibited in novel mechanisms-of-action, and their identification paves the way for further target identification studies.