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Development of Novel Chemotherapeutics against bacteria and protozoa
Infectious diseases including acute respiratory infections, diarrhoeal diseases, measles, AIDS, malaria and tuberculosis remain the main cause of death worldwide (~85% of the mortality). In addition, several pathogenic bacteria and protozoa cause high rates of morbidity with social and economic consequences. Resistance to first-line drugs in the pathogens causing these diseases is widely spread. The massive increases in trade and human mobility as a consequence of globalization have enabled the rapid spread of infectious agents, including those that are drug resistant. Antibiotic resistance is responsible for approximately 100,000 deaths in the United States, caused by hospital-acquired infections per year at an estimated annual cost of $23 billion.
Development of new classes of broad-spectrum chemotherapeutic agents based on new targets is critically needed to overcome drug-resistance and unwanted side-effects to the current therapeutics for infectious diseases. Theoretically, drug targets that are absent in or different from the human host substantially decrease the potential of unwanted side effects, and drugs against these targets are likely to be safe in pregnant women, elder patients and children which are the most susceptible population to severe infectious disease. The methylerythritol phosphate (MEP) pathway for isoprenoid biosynthesis had become an excellent drug target against bacteria and a parasite since it is absent in humans and is essential for survival of pathogens that rely on this pathway for isoprenoids supply. We are exploring two pathways to obtain specific inhibitors against the MEP pathway: 1) screening of natural extracts and 2) drug design using structure-based design, molecular docking, and ligand-based approaches. Moreover, our laboratory uses the liquid chromatography in tandem with mass spectrometry-based methods for metabolite analysis, pharmacokinetics and ADME analysis.