Drugging the thiamine-diphosphate binding-site of the antibiotic target DXPS

To counter antimicrobial resistance, this thesis focuses on inhibiting 1-deoxy-D-xylulose-5-phosphate synthase (DXPS), an enzyme belonging to the bacterial MEP (2-C-methyl-D-erythritol-4-phosphate) pathway. A tailored design approach yielded drug-like inhibitors of Mycobacterium tuberculosis DXPS with solid ADMET profiles and activity against resistant strains. Druggability investigations in Deinococcus radiodurans DXPS revealed that metal-independent diphosphate sites are accessible, whereas metal-dependent sites may require different methods. Furthermore, phage display provided a peptidic DXPS inhibitor targeting the acceptor substrate site, demonstrating functional pocket overlap.