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.
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.
Amongst the many synthetic aminoglycoside analogues that were developed to regain the efficacy of this class of antibiotics against resistant bacterial strains, the 1-N-acylated analogues are the most clinically used. In this study we demonstrate that 6'-N-acylation of the clinically used compound tobramycin and 6'''-N-acylation of paromomycin result in derivatives resistant to deactivation by 6'-aminoglycoside acetyltransferase (AAC(6')) which is widely found in aminoglycoside resistant bacteria. When tested against AAC(6')- or AAC(3)-expressing bacteria as well as pathogenic bacterial strains, some of the analogues demonstrated improved antibacterial activity compared to their parent antibiotics. Improvement of the biological performance of the N-acylated analogues was found to be highly dependent on the specific aminoglycoside and acyl group. Our study indicates that as for 1-N-acylation, 6'- and 6'''-N-acylation of aminoglycosides offer an additional promising direction in the search for aminoglycosides capable of overcoming infections by resistant bacteria.
In this study, we describe the synthesis of a full set of homo- and hetero-dimers 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.
The epigenetic DNA modification 5-hydroxymethylcytosine (5-hmC) is important for the regulation of gene expression during development and in tumorigenesis. 5-hmC can be selectively glycosylated by T4 β-glucosyltransferase (β-GT); introduction of an azide on the attached sugar provides a chemical handle for isolation or fluorescent tagging of 5-hmC residues by click chemistry. This approach has not been broadly adopted because of the challenging synthesis and limited commercial availability of the glycosylation substrate, 6-deoxy-6-azido-α-D-glucopyranoside. We report the enzyme-assisted synthesis of this precursor by the uridylyltransferase from Pasteurella multocida (PmGlmU). We were able to directly label 5-hmC in genomic DNA by an enzymatic cascade involving successive action of PmGlmU and β-GT. This is a facile and cost-effective one-pot chemoenzymatic methodology for 5-hmC analysis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.