OBJECTIVES: Neomycin B exhibits poor antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, while kanamycin A shows weak activity against MRSA, methicillin-resistant 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: Seven polyguanidinylated neomycin B-lipids differing in the nature of the lipid tail and two cationic kanamycin 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: These findings suggest that lipid conjugation of neomycin B- and kanamycin A-derived cationic lipids provides a general tool to enhance the antibacterial activity of these two aminoglycosides against resistant strains.
OBJECTIVES:Neomycin B exhibits poor antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, while kanamycin A shows weak activity against MRSA, methicillin-resistant 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: Seven polyguanidinylated neomycin B-lipids differing in the nature of the lipid tail and two cationic kanamycin 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: These findings suggest that lipid conjugation of neomycin B- and kanamycin A-derived cationic lipids provides a general tool to enhance the antibacterial activity of these two aminoglycosides against resistant strains.
Authors: Liuwei Jiang; Derrick Watkins; Yi Jin; Changjun Gong; Ada King; Arren Z Washington; Keith D Green; Sylvie Garneau-Tsodikova; Adegboyega K Oyelere; Dev P Arya Journal: ACS Chem Biol Date: 2015-02-23 Impact factor: 5.100