The Road Not Taken

Antimicrobial resistance (AMR) is a global health threat, decreasing the efficacy of current treatments and putting at risk the progress of modern medicine. The dried-up drug pipeline, together with the rise of resistant pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum, calls for the use of different strategies in the discovery of the next generation of antimicrobials. This thesis explores the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway as a promising source of new antimicrobial targets, given its essential role in many pathogens but absence in humans. The work focuses on two key enzymes of the MEP pathway—1-deoxy-D-xylulose 5-phosphate synthase (DXPS) and 1-deoxy-D xylulose 5-phosphate reductoisomerase (DXR)—to address both structural knowledge gaps and drug design challenges. The research includes structural studies of DXPS from M. tuberculosis and P. falciparum, revealing critical features for future inhibitor development and mechanistic studies. In addition, new analogs of the known DXR inhibitor fosmidomycin were synthesized and evaluated to improve its antimicrobial potency. These findings not only advance the structural knowledge of the DXPS enzyme but also contribute to the design of new drugs against AMR pathogens.