Dual‐Functional Antibiotic Adjuvants Based on Antibacterial Polyesters With Guanidinium and Boronic Acid Motifs

This study addresses the challenge of antimicrobial resistance in Gram-negative bacteria by developing a novel class of biodegradable polymeric antibiotic adjuvants. We have engineered cationic polyesters functionalized with guanidinium and phenylboronic acid (PBA) groups through the one-pot thiol-Michael addition post-modification to create a dual-targeting mechanism against the bacterial outer membrane (OM). This design combines the membrane-disruptive action of guanidinium with the specific binding capability of PBA to lipopolysaccharides. The relationships between structure of the polymers and their antibacterial ability or cytocompatibility were explored. The optimized polymer, G95-BA5, exhibited potent intrinsic bactericidal activity and good biocompatibility. It also demonstrated remarkable in vitro synergy with rifampicin against multidrug-resistant pathogens, achieving fractional inhibitory concentration indices as low as 0.06 by significantly enhancing the outer membrane permeability. In a lethal murine peritonitis model, the combination of G95-BA5 and rifampicin provided 100% survival, drastically reduced bacterial burden in vital organs, and controlled systemic inflammation. This work establishes an effective polymer platform for overcoming the OM permeability-based resistance and revitalizing existing antibiotics.