6′′-Thioether Tobramycin Analogues: Towards Selective Targeting of Bacterial Membranes


  • This work was supported by the Life Sciences Institute and the College of Pharmacy at the University of Michigan (S.G.-T.), by a grant from the Firland Foundation (S.G.-T.), and by a National Institutes of Health (NIH) Grant AI090048 (S.G.-T.). This work was also supported by a grant from the United States-Israel Binational Science Foundation (BSF), Jerusalem, Israel (Grant 2008017, S.G.-T. and M.F.), and by the FP7-PEOPLE-2009-RG Marie Curie Auction: Reintegration Grants (Grant 246673, M.F.). We thank Profs. David H. Sherman and Philip C. Hanna (University of Michigan), Itzhak Ofek and Dani Cohen (Tel Aviv University), Doron Steinberg (The Hebrew University of Jerusalem), and Paul J. Hergenrother (University of Illinois at Urbana-Champaign) for the gift of bacterial strains used herein. We thank Prof. Timor Baasov and Dana Atia-Gilkin (Shulich Faculty of Chemistry, Technion, Israel Institute of Technology) for their assistance and guidance with the luciferase assay.


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Amphiphilic tobramycin analogues with potent antibacterial activity against tobramycin-resistant bacteria were synthesized. Most analogues were found to be less prone to deactivation by aminoglycoside-modifying enzymes than tobramycin. These compounds target the bacterial membrane rather than the ribosome (see picture). The lipophilic residue of these analogues is key to their antibacterial potency and selectivity towards bacterial membranes.