Structure aided design of chimeric antibiotics.

Article Details

Citation

Copy to clipboard

Karoli T, Mamidyala SK, Zuegg J, Fry SR, Tee EH, Bradford TA, Madala PK, Huang JX, Ramu S, Butler MS, Cooper MA

Structure aided design of chimeric antibiotics.

Bioorg Med Chem Lett. 2012 Apr 1;22(7):2428-33. doi: 10.1016/j.bmcl.2012.02.019. Epub 2012 Feb 22.

PubMed ID

22406152 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Trimethoprim	Dihydrofolate reductase	IC 50 (nM)	123	N/A	N/A	Details