Researcher(s)
- Gabriel Ma, Biomedical Engineering, University of Delaware
Faculty Mentor(s)
- Karl Schmitz, Biochemistry, University of Delaware
Abstract
Tuberculosis (TB) remains the deadliest infectious disease globally, causing approximately 1.5 million deaths annually. The emergence of antibiotic-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of TB, underscores the urgent need for new therapeutic strategies. Clp proteases, essential for Mtb survival through their role in protein quality control, represent promising antibacterial targets. These proteases comprise a protein unfoldase (ClpC1 or ClpX) and a barrel-shaped peptidase (ClpP1 and ClpP2), with the unfoldase recognizing, unraveling, and translocating substrates into the peptidase barrel for degradation. Targeting Clp proteases disrupts critical cellular processes in Mtb, making these enzymes viable candidates for novel drug development. This study, conducted in Dr. Schmitz’s lab, aims to explore the biochemical interactions between ClpC1-targeting compounds and ClpC1 activity, contributing to the fight against drug-resistant TB. The research focuses on two primary objectives: elucidating how various compounds modulate ClpC1 ATPase activity and investigating their impact on ClpC1-mediated proteolysis of diverse substrates. Absorbance-based measurements of ATPase activity and fluorescence-based proteolysis assays will be employed to monitor these interactions under controlled conditions. By analyzing the effects of compounds such as cyclomarin, ecumicin, and metamarin on ClpC1 activity and substrate degradation, this study seeks to identify potential inhibitors of ClpC1 function. The findings will provide valuable insights into the biochemical pathways targeted by these compounds and their efficacy as anti-TB agents, paving the way for the development of targeted and effective treatments against drug-resistant Mtb strains.