Antibacterial activity of guanidinylated neomycin B- and kanamycin A-derived amphiphilic lipid conjugates

Objectives: Neomycin B exhibits poor antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, while kanamycin A shows weak activity against MRSA, methicillinresistant Staphylococcus epidermidis (MRSE) and P. aeruginosa. The main purpose of this work was to study whether lipid conjugation of guanidinylated neomycin B- and kanamycin A-derived cationic headgroups could restore antibacterial activity against neomycin B- and kanamycin A-resistant strains, while retaining antibacterial activity against non-resistant strains. Methods: SevenpolyguanidinylatedneomycinB-lipidsdifferinginthenatureofthelipidtailandtwocationickanamycin A-lipids were prepared, and their in vitro activity was assessed against a variety of neomycin B- and kanamycin A-resistant and neomycin B- and kanamycin A-non-resistant Gram-positive and Gram-negative strains. Results: Conjugation of neomycin B- and kanamycin A-derived polyamine or polyguanidinylated headgroups to hydrophobic C16 or C20 lipid tails restored the anti-MRSA activity of both aminoglycosides and the anti-MRSE activity of kanamycin A. Polyguanidinylation of the neomycin B-derived headgroup lowers the hydrophobic requirement of the lipid tail segment to provide broad-spectrum antibacterial activity from C16 to C12. Moreover, guanidinylation of the polycationic headgroup in neomycin B-derived cationic lipids enhances antibacterial activity against a neomycin B-, kanamycin A- and gentamicin-resistant P. aeruginosa strain, and reduces haemolytic activity. Conclusions:ThesefindingssuggestthatlipidconjugationofneomycinB-andkanamycinA-derivedcationiclipids provides a general tool to enhance the antibacterial activity of these two aminoglycosides against resistant strains.