Synthesis and antibacterial activity of amphiphilic lysine-ligated neomycin B conjugates |
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Authors: | Bera Smritilekha Zhanel George G Schweizer Frank |
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Institution: | aDepartment of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2;bDepartment of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada R3E 3P4 |
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Abstract: | Amphiphilic lysine-ligated neomycin B building blocks were prepared by reductive amination of a protected C5″-modified neomycin B-based aldehyde and side chain-unprotected lysine or lysine-containing peptides. It was demonstrated that a suitably protected lysine-ligated neomycin B conjugate (NeoK) serves as a building block for peptide synthesis, enabling incorporation of aminoglycoside binding sites into peptides. Antibacterial testing of three amphiphilic lysine-ligated neomycin B conjugates against a representative panel of Gram-positive and Gram-negative strains demonstrates that C5″-modified neomycin-lysine conjugate retains antibacterial activity. However, in most cases the lysine-ligated neomycin B analogs display reduced potency against Gram-positive strains when compared to unmodified neomycin B or unligated peptide. An exception is MRSA where an eightfold enhancement was observed. When compared to unmodified neomycin B, the prepared lysine-neomycin conjugates exhibited a 4–8-fold enhanced Gram-negative activity against Pseudomonas aeruginosa and up to 12-fold enhanced activity was observed when compared to unligated reference peptides. |
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Keywords: | Antimicrobial peptides Glycopeptides Aminoglycosides Antibacterials |
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