title: Design, synthesis, and evaluation of novel fluoroquinolone-aminoglycoside hybrid antibiotics.
abstract: A series of new hybrid structures containing fluoroquinolone (ciprofloxacin) and aminoglycoside (neomycin) antibiotics linked via 1,2,3-triazole moiety were designed and synthesized, and their antibacterial activities were determined against both Gram-negative and Gram-positive bacteria, including resistant strains. The nature of spacers in both the ciprofloxacin and neomycin parts greatly influenced the antibacterial activity. The majority of hybrids was significantly more potent than the parent neomycin and overcame most prevalent types of resistance associated with aminoglycosides. Selected hybrids inhibited bacterial protein synthesis with the potencies similar to or better than that of neomycin and were up to 32-fold more potent inhibitors than ciprofloxacin for the fluoroquinolone targets, DNA gyrase and toposiomerase IV, indicating a balanced dual mode of action. Significant delay of resistance formation was observed in both E. coli and B. subtilis to the treatment with ciprofloxacin-neomycin hybrid in comparison to that of each drug separately or their 1:1 mixture.
authors.affiliation: The Edith and Joseph Fisher Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry, TechnionIsrael Institute of Technology, Haifa 32000, Israel.
authors.forename: Varvara
authors.initials: V
authors.lastname: Pokrovskaya
authors.forename: Valery
authors.initials: V
authors.lastname: Belakhov
authors.forename: Mariana
authors.initials: M
authors.lastname: Hainrichson
authors.forename: Sima
authors.initials: S
authors.lastname: Yaron
authors.forename: Timor
authors.initials: T
authors.lastname: Baasov
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D005601:Framycetin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011500:Protein Synthesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D011500:Protein Synthesis Inhibitors; D059005:Topoisomerase II Inhibitors; D005601:Framycetin; D002939:Ciprofloxacin; D027101:DNA Topoisomerase IV