Presenter: Karla Pena
Authors: Karla Pena, Brady Williams, Nathan Goldfarb
Faculty Advisor: Nathan Goldfarb
Institution: Utah Valley University
Tuberculosis (TB) remains an insidious scourge of civilization. The causative agent, Mycobacterium tuberculosis (Mtb), is a global health crisis, and TB ranks as the second leading cause of death from an infectious disease worldwide after the human immunodeficiency virus (HIV). In 2020, there were approximately 1.5 million deaths reported from TB and an estimated 10 million new cases of TB. Consequently, there is an extremely urgent need for the discovery of new therapeutics effective against both drug resistant and nondrug resistant strains of TB. The product of the Rv2224c gene, Hip1 (hydrolase important for pathogenesis), is a Mtb cell-wall associated serine hydrolase that plays an important role in the pathogenic strategies of Mtb cell envelop maintenance and the dampening of host cell proinflammatory responses. Functional studies indicate that Hip1 is a promising target for drug discovery. In fact, mice infected with a Hip1 mutant strain survive significantly longer than wild-type Mtb-infected mice and exhibit mild lung immunopathology despite high bacterial burdens. Here we present the expression, purification, and crystallization of Hip1. We complexed Hip1 with several potent Hip1 inhibitors developed in our lab. Our goal is to collect diffraction data from these crystals in order to solve the first high-resolution structure of Hip1 bound with an active site-directed ligand. This structural information will be instrumental in refining our lead compounds for pharmacological liabilities.