Infectious diseases stand out as public health problem worldwide and represent a major cause of death in the human population, especially in less developed countries. Tuberculosis is still ranked among the three infectious diseases that kill most in the world due to the emergence of drug-resistant strains, the association with HIV and long treatment period. However, there no a solid investment of pharmaceutical companies in the search for new therapies due to the prospect of low financial returns. Thus, the survey of public funds is essential for the development of new drugs and may be held in partnerships with major pharmaceutical companies. For this, a strategy is the development of inhibitors of the infectious agent enzymes or enzymes which are also conserved in humans, but significant differences that may lead to the development of specific molecules. The folate synthesis pathway presents both types of enzymes, and drugs that inhibit its two enzymes have been used for decades to treat several types of infections, and no effective inhibitors for this pathway in the treatment of tuberculosis. In this project, we intend to use the technique fragment based drug discovery (FBDD) to identify relatively simple molecules that can be chemically modified for the generation of potent inhibitors of folate pathway enzymes in Mycobacterium tuberculosis. Thus, a variety of biophysical and crystallographic techniques will be applied in screening and validation of candidate small molecules. The modification or addition of functional groups to fragments identified will be held by research groups in the field of organic synthesis. Thus, proposes to study two enzymes of the pathway, these being the dihydropteroate synthase (DHPS) and dihydrofolate synthase (DHFR) in order to assist in the development of new drugs against tuberculosis.
News published in Agência FAPESP Newsletter about the scholarship: