Multi-Hydrogen Bonding on Quaternized-Oligourea Receptor Facilitated Its Interaction with Bacterial Cell Membranes and DNA for Broad-Spectrum Bacteria Killing.

Herein, we report a new strategy for the design of antibiotic agents based on the electrostatic interaction and hydrogen bonding, highlighting the significance of hydrogen bonding and the increased recognition sites in facilitating the interaction with bacterial cell membranes and DNA. A series of quaternary ammonium functionalized urea-based anion receptors were studied. While the monodentate mono-urea M1, bisurea M2, and trisurea M3 failed to break through the cell membrane barrier and thus could not kill bacteria, the extended bidentate dimers D1-D3 presented gradually increased membrane penetrating capabilities, DNA conformation perturbation abilities, and broad-spectrum antibacterial activities against E. coli, P. aeruginosa, S. aureus, E. faecalis, and S. epidermidis.

A biomimetic peptide-drug supramolecular hydrogel as eyedrops enables controlled release of ophthalmic drugs.

The rapid clearance of instilled drugs from the ocular surface due to tear flushing and excretion results in low drug bioavailability, necessitating the development of new drug delivery routes. Here, we generated an antibiotic hydrogel eye drop that can extend the pre-corneal retention of a drug after topical instillation to address the risk of side effects (e.g., irritation and inhibition of enzymes), resulting from frequent and high-dosage administrations of antibiotics used to obtain the desired therapeutic drug concentration. The covalent conjugation of small peptides to antibiotics (e.g., chloramphenicol) first endows the self-assembly ability of peptide-drug conjugate to generate supramolecular hydrogels. Moreover, the further addition of calcium ions, which are also widely present in endogenous tears, tunes the elasticity of supramolecular hydrogels, making them ideal for ocular drug delivery. The in vitro assay revealed that the supramolecular hydrogels exhibited potent inhibitory activities against both gram-negative (e.g., Escherichia coli) and gram-positive (e.g., Staphylococcus aureus) bacteria, whereas they were innocuous toward human corneal epithelial cells. Moreover, the in vivo experiment showed that the supramolecular hydrogels remarkably increased pre-corneal retention without ocular irritation, thereby showing appreciable therapeutic efficacy for treating bacterial keratitis. This work, as a biomimetic design of antibiotic eye drops in the ocular microenvironment, addresses the current issues of ocular drug delivery in the clinic and further provides approaches to improve the bioavailability of drugs, which may eventually open new directions to resolve the difficulty of ocular drug delivery. STATEMENT OF SIGNIFICANCE: Herein, we present a biomimetic design for antibiotic hydrogel eye drops mediated by calcium ions (Ca2+) in the ocular microenvironment, which can extend the pre-corneal retention of antibiotics after topical instillation. The mediation of Ca2+ which is widely present in endogenous tears, tunes the elasticity of hydrogels, making them ideal for ocular drug delivery. Since increasing the ocular retention of antibiotic eye drops enhances its action and reduces its adverse effects, this work may lead to an approach of peptide-drug-based supramolecular hydrogel for ocular drug delivery in clinics to combat ocular bacterial infections.