Naturally inspired chimeric quinolone derivatives to reverse bacterial drug resistance

Antimicrobial resistance poses an urgent threat to global health, underscoring the critical need for new antibacterial drugs. Ciprofloxacin, a third-generation quinolone antibiotic, is used to treat different types of bacterial infections; however, it often results in the rapid emergence of resistance in clinical settings. Inspired by low susceptibility to antimicrobial resistance of natural antimicrobial peptides, we herein propose a host defense peptide-mimicking strategy for designing chimeric quinolone derivatives which may reduce the likelihood of antibacterial resistance. This strategy involves the incorporation of deliberately designed amphiphilic moieties into ciprofloxacin to mimic the structural characteristics and resistance-evading properties of host defense peptides. A resulting chimeric compound IPMCL-28b, carrying a rigid linker and three cationic amino acids along with a lipophilic acyl n-decanoyl tail, exhibited potent activity against a panel of multidrug-resistant bacterial strains by endowing the ciprofloxacin derivatives with additional ability to disrupt bacterial cell membranes. Molecular dynamics simulations showed that IPMCL-28b demonstrates significantly stronger disruptive interactions with cell membranes than ciprofloxacin. This compound not only demonstrated high selectivity with low hemolysis side effect, but also significantly reduced the likelihood of resistance development compared with ciprofloxacin. Excitingly, IPMCL-28b demonstrated highly enhanced in vivo antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) with a 99.99 % (4.4 log) reduction in skin bacterial load after a single dose. These findings highlight the potential of host defense peptides-mimicking amphiphilic ciprofloxacin derivatives to reverse antibiotic resistance and mitigate the development of antimicrobial resistance.