Using Fragment-based Drug Discovery (FBDD) to identify selective inhibitors against folate pathway enzymes from pathogenic microorganisms

Infectious diseases are among the leading causes of death of humankind and the emergence of resistance to the most common antimicrobial is aggravating this problem. Resistance to antimicrobials is a global issue and several predictions indicate that infectious diseases will become the major cause of mortality by 2050. Thus, the research in the discovery of new antimicrobials became a priority in several countries, including UK. Among the microorganisms, the so-called "ESKAPE" group, which includes Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp., and mycobacteria species including M. tuberculosis have received considerable attention from several public sectors. These bacteria have a concern for healthcare, and they are generally associated with nosocomial infectious or are of difficult treatment with just few antimicrobial choices. In addition to the bacterial problem, diseases caused by the fungi Candida auris, an emerging pathogen firstly reported in 2009 and now spready globally, is also alarming because of its outbreaks in the healthcare setting, its innate resistance to most of antifungal drugs and its drastic resilience under hygiene and infection control methods. In face of this problem, we would like to apply the strategy of Fragment Based Drug Discovery to enzymes involved in the folate metabolism of different aetiological agents of infectious diseases, including M. tuberculosis, A. baumannni and C. auris. Using the integration of several biophysical techniques, including crystallography, isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR) in combination with computational techniques and organic chemistry, we expect to evolve series of compounds with high affinity and selectivity based on previously identified and characterised molecules (fragments) that target the enzyme Dihydrofolate Reductase from these pathogens. We also expect that these molecules have a poor effect on the human enzymes involved in folate metabolism. This project involves an intensive collaboration with Prof. Chris Abell group from the University of Cambridge, who gives strong support on organic chemistry synthesis strategies.