Enantiomer-Dependent Supramolecular Antibacterial Therapy for Drug-Resistant Bacterial Keratitis

Abstract

Bacteria have the potential to exhibit divergent stereochemical preferences for different levels of chiral structures, including from molecule, supramolecule, to nanomicroscale helical structure. Accordingly, the structure–activity relationship between chirality and bactericidal activity remains uncertain. In this study, we seek to understand the multivalent molecular chirality effect of chiral supramolecular polymers on antibacterial activity. Two n-butylazobenzene-modified l- and d-tripeptides (abbreviated C₄Azo-l-VKK–OH and C₄Azo-d-VKK–OH) were synthesized and subsequently self-assembled in water into chiral supramolecular polymers (designated l-Fiber and d-Fiber, respectively). The l-Fiber and d-Fiber displayed comparable nonhelical nanofiber morphologies but exhibited opposite multivalent molecular chirality. A comparative study demonstrated that the l-Fiber exhibited a markedly higher affinity for bacteria, thereby demonstrating significantly enhanced bactericidal efficiency against methicillin-resistant Staphylococcus aureus (MRSA) in comparison to that of the d-Fiber. Following disassembly into monomers via host–guest chemistry, the bactericidal potency of both the l-Fiber and d-Fiber was found to be almost lost, suggesting the multivalent molecular chirality effect. Of note, the l-Fiber exhibited superior efficacy in curing MRSA-infected keratitis in comparison to the d-Fiber. These findings highlight the importance of multivalent molecular chirality in the design and development of chiral supramolecular polymers for antibacterial applications. This research also presents an effective chiral supramolecular antibacterial strategy for the treatment of drug-resistant bacteria-infected keratitis.