Conjugation of Antibiotics to Peptidomimetics Enhances Antimicrobial Spectrum of Activity

Background/Objectives: Antimicrobial conjugates have attracted considerable interest in addressing the threat of antimicrobial resistance by minimising the likelihood of resistance onset. Antimicrobial peptide mimic-antibiotic conjugates offer a unique strategy to revitalise current clinical agents through increased membrane permeabilisation, prolonging the longevity of traditional antibiotics while broadening the spectrum of activity of the AMP mimic. Methods: This study explored non-cleavable, enzyme-cleavable, and pH-cleavable linked conjugates between an anthranilamide-based peptide mimic and current clinically available antibiotics to assess the viability of conjugation in enhancing antimicrobial activity as measured through MIC assays. Cleavage studies were conducted to assess the stimulus susceptibility of relevant compounds. Results: Four amide-linked non-cleavable conjugates were synthesised. Of these, a primary amide-linked conjugate between ciprofloxacin and the peptidomimetic had the most significant activity with an MIC of 15.6 µM towards Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa, and an MIC of 7.8 µM towards Gram-negative Escherichia coli. A hydrazone-based pH-sensitive linker system was synthesised and had an MIC of 15.6 µM towards Gram-negative E. coli. Finally, an enzyme-cleavable cephalosporin conjugate system was investigated, which offered a unique method for the specific treatment of resistant bacterial strains. Cleavage studies of this conjugate suggested rapid degradation of the β-lactam ring and release of the subunit. Conclusions: This work presents conjugate systems between peptide mimics and antibiotics as a new, promising strategy to broaden the antimicrobial spectrum of novel antimicrobial agents.