Researcher(s)
- Sarah Janney, Chemistry, University of Delaware
Faculty Mentor(s)
- Joseph Fox, Chemistry and Biochemistry, University of Delaware
Abstract
Antibiotic resistance has become a major concern in public health as bacterial infections become increasingly difficult to treat. According to the World Health Organization, antimicrobial resistance is one of the top global health threats to date, contributing to 4.95 million deaths.(1) As a result, there has been a major demand for novel modes of targeting microbes or sensitizers to restore the efficacy of existing antibiotics. Recently, the incorporation of tetrazine (Tz) into the bacterial cell wall was achieved by dosing bacteria that produce recycling enzymes, AmgK and MurU, with a fatal dose of fosfomycin, which inhibits de novo UDP-N-acetylglucosamine production, in the presence of minimalist Tz N-acetyl muramic acid (HTzNAM).(2) These conditions force the bacteria to uptake and utilize HTzNAM in bacterial cell wall biosynthesis in order to survive. The rapid kinetics of the Tz- trans-Cyclooctene (TCO) ligation enables Tz-remodeled bacteria to undergo ultrafast live labeling with a TCO reaction partner, opening the door to a wide array of applications. This work aims to investigate the Tz-TCO ligation as a mode of action for novel antimicrobial therapies. We envision that treatment of Tz-remodeled bacteria with synthetically accessible TCOs containing reactive handles, such as aTCO-N-Hydroxysuccinimide ester (aTCO-NHS ester), will inhibit bacterial turnover and induce cellular lysis through the introduction of an unnatural peptidoglycan crosslinks.