Rational Design of ROS-Responsive, ROS-Scavenging, and Bacterial Membrane-Disrupting Self-Antibacterial...

The rampant abuse of antibiotics has accelerated the emergence of resistant bacteria, making infections caused by such pathogens a major challenge to effective clinical management and patient prognosis. Self-antibacterial supramolecular gels that operate via bacterial membrane disruption represent a highly promising therapeutic strategy. In this study, we designed and synthesized reactive oxygen species (ROS)-responsive low-molecular-weight gelators (LMWGs) using a bottom-up approach, based on intrinsic antibacterial synthons and an ROS-cleavable thioacetal linker. The structures of the gelators were confirmed by proton nuclear magnetic resonance (¹H NMR) spectroscopy and high-resolution mass spectrometry (HRMS). Their gelation behavior, critical gelation concentration (CGC), and self-assembly mechanism were systematically investigated. The resulting supramolecular gel was thoroughly evaluated for its rheological properties, ROS responsiveness, ROS-scavenging capability, antibiotic-loading capacity, and controlled drug-release profile. Biocompatibility and hemocompatibility were assessed using the CCK-8 assay and hemolysis assay, respectively. The antibacterial efficacy of both blank and ciprofloxacin hydrochloride (CIP·HCl)-loaded gels against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) was examined via bacterial adhesion tests and plate colony counting. Remarkably, the blank supramolecular gel exhibited potent antibacterial and bactericidal activity against both strains, with efficacy comparable to that of the CIP·HCl-loaded gel─a finding further supported by inhibition zone assays. Investigations into the antibacterial mechanism revealed significant alterations in bacterial membrane morphology and membrane potential, along with the release of intracellular DNA. Notably, owing to this membrane-disruptive action, the blank gel also demonstrated substantial efficacy against methicillin-resistant Staphylococcus aureus (MRSA). This work establishes that the rational design of LMWGs for targeted membrane disruption provides a viable and innovative platform for developing self-antibacterial supramolecular gels against drug-resistant bacterial infections.