Design and synthesis of novel inhibitors of the anti-infective target IspE

Due to the current antimicrobial resistance crisis, addressing underexplored targets to afford anti-infective compounds with novel modes of action is urgently needed. Antimicrobial resistance not only poses a threat to public health, but is a substantial cost burden on the healthcare system. This proposal focuses on the design and synthesis of novel inhibitors of the target 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase (IspE). IspE catalyzes the fourth step in the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway which is essential for medically relevant pathogens (e.g., Enterobacter coli, Klebsiella pneumoniae, Mycobacterium tuberculosis and Pseudomonas aeruginosa) but entirely absent in humans, making this enzyme a promising drug target. We will initially explore drug fragments through the screening of carefully constructed fragment libraries, followed by hit-to-lead optimization for promising compounds. Target confirmation will be performed using a biologically active small-molecule photo-crosslinking probe and a crystal structure of IspE obtained in complex with a promising inhibitor. The investigation of potential for therapeutic intervention via inhibition of IspE will result in several potent inhibitors, enhancing the knowledge of this underexplored enzyme target and opening up access for further exploration of potent inhibitors. This research will greatly contribute to the discovery of novel anti-infective agents, leading to decreased morbidity and mortality in patients, economical benefits for the health care system in the European Union as well as globally.