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

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Site-Selective Displacement of Tobramycin Hydroxyls for Preparation of Antimicrobial Cationic Amphiphiles

A short site-selective strategy for the activation and derivatization of alcohols of the clinically important aminoglycoside tobramycin is reported. The choice of amine protecting group affected the site-selective conversion of secondary alcohols of tobramycin into leaving groups. Temperature-dependent, chemoselective sequential nucleophilic displacements resulted in hetero- and homodithioether tobramycin-based cationic amphiphiles that demonstrated marked antimicrobial activity and impressive membrane selectivity

Synthesis and Evaluation of Hetero- and Homodimers of Ribosome-Targeting Antibiotics: Antimicrobial Activity, in Vitro Inhibition of Translation, and Drug Resistance

In this study, we describe the synthesis of a full set of homo- and heterodimers of three intact structures of different ribosome-targeting antibiotics: tobramycin, clindamycin, and chloramphenicol. Several aspects of the biological activity of the dimeric structures were evaluated including antimicrobial activity, inhibition of in vitro bacterial protein translation, and the effect of dimerization on the action of several bacterial resistance mechanisms that deactivate tobramycin and chloramphenicol. This study demonstrates that covalently linking two identical or different ribosome-targeting antibiotics may lead to (i) a broader spectrum of antimicrobial activity, (ii) improved inhibition of bacterial translation properties compared to that of the parent antibiotics, and (iii) reduction in the efficacy of some drug-modifying enzymes that confer high levels of resistance to the parent antibiotics from which the dimers were derived

Inside Cover: 6′′‐Thioether Tobramycin Analogues: Towards Selective Targeting of Bacterial Membranes (Angew. Chem. Int. Ed. 23/2012)

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Innentitelbild: 6′′‐Thioether Tobramycin Analogues: Towards Selective Targeting of Bacterial Membranes (Angew. Chem. 23/2012)

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