Structure aided design of chimeric antibiotics

Karoli, Tomislav, Mamidyala, Sreeman K., Zuegg, Johannes, Fry, Scott R., Tee, Ernest H. L., Bradford, Tanya A., Madala, Praveen K., Huang, Johnny X., Ramu, Soumya, Butler, Mark S. and Cooper, Matthew A. (2012) Structure aided design of chimeric antibiotics. Bioorganic & Medicinal Chemistry Letters, 22 7: 2428-2433. doi:10.1016/j.bmcl.2012.02.019

Author Karoli, Tomislav
Mamidyala, Sreeman K.
Zuegg, Johannes
Fry, Scott R.
Tee, Ernest H. L.
Bradford, Tanya A.
Madala, Praveen K.
Huang, Johnny X.
Ramu, Soumya
Butler, Mark S.
Cooper, Matthew A.
Title Structure aided design of chimeric antibiotics
Journal name Bioorganic & Medicinal Chemistry Letters   Check publisher's open access policy
ISSN 1464-3405
Publication date 2012-04-01
Sub-type Article (original research)
DOI 10.1016/j.bmcl.2012.02.019
Volume 22
Issue 7
Start page 2428
End page 2433
Total pages 6
Place of publication Amsterdam, The Netherlands
Publisher Pergamon
Language eng
Formatted 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.
Keyword Chimeric antibiotics
Drug resistant bacteria
DNA gyrase
Dihydrofolate reductase
Click chemistry
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Received 19 December 2011; Revised 6 February 2012; Accepted 7 February 2012; Available online 22 February 2012

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
Institute for Molecular Bioscience - Publications
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