Inhibition of MEP pathway Isoprenoid biosynthesis

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), and malaria, caused by Plasmodium falciparum, remain amongst the world’s deadliest infectious diseases. Co-infection with other diseases such as HIV plus the emergence of many drug-resistant strains worldwide have made these infections difficult and costly to treat. New drugs are needed that will kill wild-type and drug-resistant strains of both organisms. The major challenge in developing new antimicrobial agents is to identify metabolic processes that are both required for viability and able to be targeted by small molecules. It will be achieved by coupling the synthesis of potent small molecule inhibitors acting on-target intracellularly with downstream pharmacokinetic and animal experiments. Dxr and MEP are essential for Mtb and P. falciparum survival, and the pathway is absent in humans. Current antimicrobial drugs do not work through a Dxr (or MEP) mechanism. Development of Dxr inhibitors as lead compounds against TB and malaria would be therapeutically valuable. Previous work has resulted in several compound series that potently inhibit Dxr, kill both Mtb and P. falciparum-infected cells, act on-target intracellularly, and kill Plasmodium infection in mice. The proposed experiments are designed to further improve the efficacy of our compounds, verify the intracellular effects of Dxr inhibition, and evaluate the therapeutic potential of the most potent inhibitors. First, based on the success in prior work, this project will synthesize a series of novel, rationally-designed phosphonic acids. To improve cell penetration, lipophilic prodrug esters will also be synthesized. Second, compounds will be assessed for inhibition and mode of binding against purified recombinant Dxr from Mtb and P. falciparum. Third, it will measure the antimicrobial activity of our compounds against wild-type and drug-resistant strains. This project will confirm the intracellular, on-target effects of the compounds. The most promising compounds will be evaluated in pharmacokinetics (PK) and animal efficacy assays. Overall, the experiments outlined in this proposal will result in potent antimicrobial compounds against both Mtb and P. falciparum and may provide a platform for further lead molecule development.

NIH Porject details

Drug-based Strategies
Product Development

Feb 2016 — Jan 2023

$2.61M

United States