Faculty Affairs and Academic Programs
Matthew Griffin
Life Sciences; Agriculture and Veterinary Sciences
Chemistry, Pharmaceutical Sciences, and Molecular Biology and Biochemistry
UC Irvine
Targeting Peptidoglycan Remodeling to Combat the Threat of Multidrug Resistant Bacteria
Antibiotic resistance is a rising worldwide threat to human health that may lead to millions of unnecessary deaths if not curbed in the coming decades. Despite the clear urgency, the identification of new antibiotic and antivirulence agents has not kept pace with the explosive emergence of new multidrug resistant bacterial strains. Many of the oldest and most successful antibiotic classes disrupt the assembly of cell wall peptidoglycan (PG), a polymeric sugar used by virtually all bacteria to protect themselves from the environment. However, the disassembly of PG, which is necessary for bacterial growth and division, has been almost completely overlooked as a target for small molecule drugs. Unfortunately, the mechanisms of PG degradation in non-model organisms have not been well defined, which has prevented the identification, selection, and screening of new drug targets. In our lab, we have developed a new bioinformatic approach to comprehensively identify the machinery used by bacteria to remodel and degrade PG. In this proposal, we will utilize our new methodology to identify PG-degrading enzymes used by the most widespread multidrug resistant bacteria. Using our expertise in protein expression and PG analysis, we will characterize lead enzymes for drug discovery. Finally, we will work with our collaborators in the Paegel lab to conduct preliminary screens using DNA-encoded compound libraries to identify new pharmacophores that target these critical enzymes. Together, our pilot studies will reveal the full repertoire of targetable PG degrading enzymes across multiple pathogens and provide proof-of-concept data to target these enzymes for next-generation therapies.
