Modified non-toxic tunicamycin, TunR2: Physical and chemical properties, bioactivity, and potential for antimycobacterial formulations

Authors: Price, Neil; Jackson, Michael; Vermillion, Karl; Bannantine, John; COLOMBATTI, ALEJANDRA - Orise Fellow; NONARATH, HANNAH - Medical College Of Wisconsin; LINK, BRIAN - Medical College Of Wisconsin

Submitted to: Gordon Research Conferences
Publication Type: Abstract Only
Publication Acceptance Date: 7/22/2023
Publication Date: N/A
Citation: N/A

Interpretive Summary:

Technical Abstract: TunR2 is a novel mode-of-action antibiotic developed by the U.S. Dept of Agriculture based on the structure of the natural product tunicamycin (TUN). TunR2 is modified to minimize animal toxicity while maintaining the required antibacterial activity. In combination therapy, TunR2 is also a potent adjuvant of the beta-lactam family of antibiotics, enhancing several cephalosporins by more than 100-fold. In trials, TunR2 has shown considerable promise in pharmacokinetic studies in mouse and zebrafish model organisms. TUN are potent inhibitors of the polyprenyl-phosphate N-acetylhexosamine-1-phosphate-transferase (PNPT) superfamily, which are essential in both eukaryotes and bacteria. In eukaryotes, the PNPT homolog DPAGT1 catalyzes the first step in protein N-glycosylation, and TUN inhibition results in misfolding of glycoproteins and a lethal unfolded protein shock cellular response. The TunR2 compounds, in which the tunicaminyl N-uracil group is replaced by N-linked 5,6-dideoxyuracil, are essentially non-toxic to eukaryotes whilst maintaining potent antibacterial properties, and including the enhancement activity in combination with several, well-established beta-lactam antibiotics. We show that TunR2 has considerable promise as novel mode-of-action anti-mycobacterial agents.