Ido M. Herzog

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

Decades of widespread clinical use of the bacterial ribosome A-site targeting aminoglycosides (AGs) enhanced the evolution of resistance to these antibiotics and reduced their clinical efficacy.[1] Three modes of action lead to bacterial resistance to AGs: reduction in the intracellular concentration of the antibiotics by efflux pump proteins or through reduced membrane permeability; structural modifications of the 16S ribosomal RNA leading to reduced target affinity; and deactivation by AG-modifying enzymes (AMEs).[1c, 2] AMEs are divided into three families: AG nucleotidyltransferases (ANTs), AG phosphotransferases (APHs), and AG acetyltransferases (AACs).[1b, 3]

Cationic Pillararenes Potently Inhibit Biofilm Formation without Affecting Bacterial Growth and Viability

It is estimated that up to 80% of bacterial infections are accompanied by biofilm formation. Since bacteria in biofilms are less susceptible to antibiotics than are bacteria in the planktonic state, biofilm-associated infections pose a major health threat, and there is a pressing need for antibiofilm agents. Here we report that water-soluble cationic pillararenes differing in the quaternary ammonium groups efficiently inhibited the formation of biofilms by clinically important Gram-positive pathogens. Biofilm inhibition did not result from antimicrobial activity; thus, the compounds should not inhibit growth of natural bacterial flora. Moreover, none of the cationic pillararenes caused detectable membrane damage to red blood cells or toxicity to human cells in culture. The results indicate that cationic pillararenes have potential for use in medical applications in which biofilm formation is a problem.

Design of membrane targeting tobramycin-based cationic amphiphiles with reduced hemolytic activity

Tobramycin-based cationic amphiphiles differing in the chemical bond linking their hydrophobic and hydrophilic parts were synthesized and biologically evaluated. Several compounds demonstrated potent antimicrobial activities compared to the parent drug. One analogue exhibited a significant reduction in red blood cells hemolysis, demonstrating that it is possible to maintain the antimicrobial potency of these molecules while reducing their undesired hemolytic effect through chemical modifications.

Tobramycin and Nebramine as Pseudo‐oligosaccharide Scaffolds for the Development of Antimicrobial Cationic Amphiphiles

Antimicrobial cationic amphiphiles derived from aminoglycoside pseudo-oligosaccharide antibiotics interfere with the structure and function of bacterial membranes and offer a promising direction for the development of novel antibiotics. Herein, we report the design and synthesis of cationic amphiphiles derived from the pseudo-trisaccharide aminoglycoside tobramycin and its pseudo-disaccharide segment nebramine. Antimicrobial activity, membrane selectivity, mode of action, and structure-activity relationships were studied. Several cationic amphiphiles showed marked antimicrobial activity, and one amphiphilic nebramine derivative proved effective against all of the tested strains of bacteria; furthermore, against several of the tested strains, this compound was well over an order of magnitude more potent than the parent antibiotic tobramycin, the membrane-targeting antimicrobial peptide mixture gramicidin D, and the cationic lipopeptide polymyxin B, which are in clinical use.

Di-N-Methylation of Anti-Gram-Positive Aminoglycoside-Derived Membrane Disruptors Improves Antimicrobial Potency and Broadens Spectrum to Gram-Negative Bacteria.

The effect of di-N-methylation of bacterial membrane disruptors derived from aminoglycosides (AGs) on antimicrobial activity is reported. Di-N-methylation of cationic amphiphiles derived from several diversely structured AGs resulted in a significant increase in hydrophobicity compared to the parent compounds that improved their interactions with membrane lipids. The modification led to an enhancement in antibacterial activity and a broader antimicrobial spectrum. While the parent compounds were either modestly active or inactive against Gram-negative pathogens, the corresponding di-N-methylated compounds were potent against the tested Gram-negative as well as Gram-positive bacterial strains. The reported modification offers a robust strategy for the development of broad-spectrum membrane-disrupting antibiotics for topical use.

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.

Di-alkylated paromomycin derivatives: targeting the membranes of gram positive pathogens that cause skin infections.

A collection of paromomycin-based di-alkylated cationic amphiphiles differing in the lengths of their aliphatic chain residues were designed, synthesized, and evaluated against 14 Gram positive pathogens that are known to cause skin infections. Paromomycin derivatives that were di-alkylated with C7 and C8 linear aliphatic chains had improved antimicrobial activities relative to the parent aminoglycoside as well as to the clinically used membrane-targeting antibiotic gramicidin D; several novel derivatives were at least 16-fold more potent than the parent aminoglycoside paromomycin. Comparison between a di-alkylated and a mono-alkylated paromomycin indicated that the di-alkylation strategy leads to both an improvement in antimicrobial activity and to a dramatic reduction in undesired red blood cell hemolysis caused by many aminoglycoside-based cationic amphiphiles. Scanning electron microscopy provided evidence for cell surface damage by the reported di-alkylated paromomycins.