The road not taken: unveiling the MEP pathway to tackle antimicrobial resistance
Antimicrobial resistance (AMR) is a global health threat, decreasing the efficacy of current treatments and putting at risk the progress of modern medicine. The small number of new antibiotics, together with the rise of resistant bacteria 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 bacteria but absence in humans. The work focuses on two key proteins of the MEP pathway—1-deoxy-D-xylulose 5-phosphate synthase (DXPS) and 1-deoxy-D xylulose 5-phosphate reductoisomerase (DXR)—to not only see how they look like but also to discover new drugs that can be used against them.
The research includes structural studies of DXPS from M. tuberculosis and P. falciparum, revealing new aspects of the protein that can be used for future studies and that will help to identify new drugs. 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.