Synthesis and Synergistic Antimicrobial Efficacy of Covalent Conjugates Composed of Epsilon-Poly-l-lysine and Beta-Lactam Antibiotics.

The increasing severity of problems posed by drug-resistant pathogens has compelled researchers to explore innovative approaches for infection prevention. Among these strategies, conjugation methods stand out for their convenience and high efficacy. In this study, multiple covalent conjugates were synthesized, incorporating the natural antimicrobial peptide epsilon-poly-l-lysine (EPL) and two commonly used β-lactam antibiotics: penicillin G or ampicillin. Enhanced antimicrobial efficacy against typical Gram-negative pathogens, along with faster kill kinetics compared to combination approaches, was demonstrated by the EPL-Ampicillin covalent conjugates. Their antimicrobial mechanism was also substantiated through SEM and fluorescence tests in this work, confirming the inheritance of membrane-disrupting properties from EPL. Furthermore, the excellent biocompatibility of the raw materials was reserved in the covalent conjugates. This simplified conjugation method holds promise for the development of infection therapeutic drugs and potentially restores the sensitivity of conventional antibiotics to drug-resistant pathogens by introducing membrane-disrupting mechanisms.