title: Structure aided design of chimeric antibiotics.
abstract: The rise of antibiotic resistance is of great clinical concern. One approach to reducing the development of resistance is to co-administer two or more antibiotics with different modes of action. However, it can be difficult to control the distribution and pharmacokinetics of two drugs to ensure both concentrations remain within the range of therapeutic efficacy whilst avoiding adverse effects. Hybrid drugs, where two drugs are linked together with a flexible linker, have been explored, but the resultant large, flexible molecules can have poor bioavailability. We have developed a chimeric approach using click chemistry where the pharmacophores of two drugs are overlapped into a single smaller, more drug-like molecule. Design and selection of compounds were assisted by in silico structural docking. We prepared a series of compounds that include candidates showing activity against the targets of both trimethoprim; dihydrofolate reductase, and ciprofloxacin; DNA gyrase and topoisomerase IV. The resultant triazole containing molecules show modest, but broad spectrum activities against drug sensitive and resistant Gram-negative and Gram-positive bacteria, with no observable cytotoxicity.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Tomislav
authors.initials: T
authors.lastname: Karoli
authors.forename: Sreeman K
authors.initials: SK
authors.lastname: Mamidyala
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuegg
authors.forename: Scott R
authors.initials: SR
authors.lastname: Fry
authors.forename: Ernest H L
authors.initials: EH
authors.lastname: Tee
authors.forename: Tanya A
authors.initials: TA
authors.lastname: Bradford
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Madala
authors.forename: Johnny X
authors.initials: JX
authors.lastname: Huang
authors.forename: Soumya
authors.initials: S
authors.lastname: Ramu
authors.forename: Mark S
authors.initials: MS
authors.lastname: Butler
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002939:Ciprofloxacin / Q000737:chemistry; D057930:Click Chemistry; D003198:Computer Simulation; D027081:DNA Gyrase / Q000737:chemistry; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors / Q000737:chemistry; D015195:Drug Design; D004352:Drug Resistance, Microbial; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry; D059005:Topoisomerase II Inhibitors; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014295:Trimethoprim / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D059005:Topoisomerase II Inhibitors; D014230:Triazoles; D002939:Ciprofloxacin; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase