Rational design and synthesis of potent aminoglycoside antibiotics against resistant bacterial strains

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 1; pp. 30 - 40
• Main Authors: Yan, Ri-Bai, Yuan, Min, Wu, Yanfen, You, Xuefu, Ye, Xin-Shan
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.01.2011; Elsevier
• Subjects: Aminoglycoside; Aminoglycoside antibiotics; Aminoglycosides - chemical synthesis; Aminoglycosides - chemistry; Aminoglycosides - pharmacology; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacteria; Bacteria - drug effects; Biological and medical sciences; Carbohydrate Sequence; Chemical modification; chemistry; Drug Design; Drug resistance; Drug Resistance, Microbial; General aspects; Kanamycin; Medical sciences; Models, Molecular; Molecular Sequence Data; Neamine; Pharmacology. Drug treatments; Chemical modification; Drug design; Antibiotics; Drug resistance; Aminoglycoside; Pseudomonadales; Enterococcus faecalis; Escherichia coli; Bacteria; Micrococcales; Pseudomonadaceae; Kanamycin; Pseudomonas aeruginosa; Micrococcaceae; Chemical synthesis; Clinical isolate; Staphylococcus aureus; Enterobacteriaceae; Treatment resistance; Biological activity; Streptococcaceae; Antibiotic; Staphylococcus epidermidis; Antibacterial agent; Klebsiella pneumoniae
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.11.065

Kanamycin B analogues were rationally designed and synthesized. Some synthetic compounds exhibited good to excellent antibiotic activity against drug-resistant bacteria. Based on the structural information of biomacromolecule–aminoglycoside complexes, a series of kanamycin B analogues were rationally designed and synthesized. A convenient approach to the construction of kanamycin derivatives, in which the C4′-position on ring I of neamine moiety was modified, was developed. Most synthetic analogues exhibited good to excellent antibiotic activity against some typical drug-resistant bacteria. The disclosed results suggested that the C4′-position of aminoglycosides such as kanamycin may be an ideal site for modification to gain new modifying enzyme-resistant aminoglycoside antibiotics.