Matthew Culyba, MD, PhD, has been awarded Catalytic Grant funding in the amount of $50,000 for a two-year award by the K Award to R Advancement Training (KARAT) Program for his proposal entitled “Molecular evaluation of the Staphylococcus aureus Rel enzyme as a therapeutic drug target to combat antibiotic tolerance.” The KARAT Program is a new Department of Medicine initiative for NIH-mentored K-awardees or other equivalent mentored Career Development Awardees (CDA) to enhance their success in obtaining their first R grant. The KARAT program provides a broad range of career development activities and academic support, including grant writing workshops, grant reviews, academic skills training, networking and peer support for K/CDA awardees.

Antimicrobial resistance is outpacing new antibiotic development, underscoring the critical need to identify novel approaches to therapy. Dr. Culyba’s proposal evaluates targeting antibiotic ‘tolerance’ as one such novel approach. His study focuses on Staphylococcus aureus Rel (RelSa), the key regulatory enzyme of the bacterial stringent response (SR), a stress-response pathway linked to antibiotic tolerant infections. In a preliminary study of 20 patients failing therapy for severe methicillin-resistant S. aureus (MRSA) infection, he identified a novel set of 5 mutations in rel that are associated with antibiotic tolerance. He and his colleagues have uncovered 11 novel mutations in the tricarboxylic acid (TCA) cycle genes, citZ and odhA, another pathway linked to antibiotic tolerance. All of these mutations are protein-altering and analysis shows they occurred at a frequency much greater than expected by chance alone and, therefore, represent adaptations to the host environment demonstrating data of clinical relevance.

The overall objective of this research is to critically evaluate RelSa as a novel anti-tolerance target for antibiotic development. Dr. Culyba anticipates delivering cutting-edge scientific insights into the SR activation mechanism and the intersection of the SR with the TCA cycle, as well as a range of new tools to study antibiotic tolerance in S. aureus, including an optimized HTS screen and characterization of new small molecule inhibitors. Knowledge of these mechanisms will provide unique insights into S. aureus tolerance pathways, which in turn will facilitate an understanding of how inhibition of this pathway could effectively eradicate persistent infections. Additionally, Dr. Culyba anticipates these data will provide proof-of-concept that RelSa can be successfully targeted for novel antimicrobial drug discovery using a HTS approach.

Please join us in congratulating Matt!