Bio-Orthogonal Chemistry and Reloadable Biomaterial Enable Local Activation of Antibiotic Prodrugs and Enhance Treatments against Staphylococcus aureus Infections

Abstract

Systemic administration of antibiotics can cause severe side-effects such as liver and kidney toxicity, destruction of healthy gut bacteria, as well as multidrug resistance. Here, we present a bio-orthogonal chemistry-based strategy toward local prodrug concentration and activation. The strategy is based on the inverse electron-demand Diels–Alder chemistry between trans-cyclooctene and tetrazine and involves a biomaterial that can concentrate and activate multiple doses of systemic antibiotic therapy prodrugs at a local site. We demonstrate that a biomaterial, consisting of alginate hydrogel modified with tetrazine, is efficient at activating multiple doses of prodrugs of vancomycin and daptomycin in vitro as well as in vivo. These results support a drug delivery process that is independent of endogenous environmental markers. This approach is expected to improve therapeutic efficacy with decreased side-effects of antibiotics against bacterial infections. The platform has a wide scope of possible applications such as wound healing, and cancer and immunotherapy.

Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups

“…3,4 These reactions have opened unprecedented possibilities in chemical biology and drug delivery. 5,6 Dissociative bioorthogonal chemistry has been applied to the on-demand dissolution of polymers and micelles, 7-9 site-specic actuation of prodrugs, [10][11][12] and control of enzyme activity in vivo. [13][14][15] Although a growing number of "click-to-release" reactions [16][17][18][19][20][21][22][23] has provided a solid foundation for applications in the life sciences, extending the reaction scope will be necessary to access the full range of capabilities.…”

Dissociative Bioorthogonal Reactions

“…Moreover, although these strategies have been confined to demonstrations on tumor models, they might be applicable to other ailments. Indeed, a recent report illustrated the possibility of using this strategy for the local delivery of antibiotics …”

“…Indeed, ar ecent report illustrated the possibility of using this strategy for the local delivery of antibiotics. [97]…”

Controlled Release of a Micelle Payload via Sequential Enzymatic and Bioorthogonal Reactions in Living Systems

“…Mejia Oneto et al. also demonstrated the bioorthogonal triggering of TCO‐based prodrugs of either anticancer or antibiotic agents by alginate hydrogel coated with Tz moieties previously injected in the targeted tissues. Very recently, Chen and Gao reported an elegant approach in which a TCO‐caged prodrug was activated in tumors by Tz‐containing supramolecular assembly selectively formed inside cancer cells over‐expressing phosphatase .…”