Maksim Royzen1 Jose Majia Oneto2

1, University at Albany, Albany, New York, United States
2, Shasqi, Inc, San Francisco, California, United States

It is estimated that 2 million patients suffer each year from antibiotic-resistant infections in the U.S. At least 23,000 die as a result of the infections according to the CDC. A bio-orthogonal chemistry-based strategy to address this problem will be presented. The strategy is termed 'catch and release’ and it involves an inverse-electron demand Diels-Alder (IEDDA) reaction between tetrazine and trans-cyclooctene (TCO). A reloadable biocompatible hydrogel, modified with tetrazine is injected in the vicinity of an infected site. Prodrugs with attenuated activity and minimal side effects, containing a releasable TCO moiety are systemically injected. When the prodrug and the hydrogel come in contact, the bio-orthogonal agents react with each other through IEDDA reaction ‘catching’ the payload. Finally, the resulting intermediate isomerizes spontaneously releasing the active antibiotic from the hydrogel to perform its therapeutic function locally. In vitro data will be presented to show that the tetrazine-modified hydrogel is stable under simulated physiological conditions and capable of activating multiple doses of model prodrugs of vancomycin and daptomycin. Meanwhile, in vivo testing proved that the ‘catch and release’ strategy is capable of local activation of therapeutically meaningful quantities of vancomycin to treat methicillin-resistant Staphylococcus aureus. Multivalency of HMT allows for the process to be repeated with multiple doses of the systemically administered prodrugs.