Potential for the Development of a New Generation of Aminoglycoside Antibiotics.

The present review summarizes recent publications devoted to aminoglycosides that study the main types of resistance to antibiotics of this class and the main directions of chemical modification aimed at overcoming the resistance or changing the spectrum of biological activity. Conjugates of aminoglycosides with various pharmacophores including amino acids, peptides, peptide nucleic acids, nucleic bases, and several other biologically active molecules and modifications resulting in other types of biological activity of this class of antibiotics are described. It is concluded that a promising research direction aimed at increasing the activity of antibiotics against resistant strains is the search for selective inhibitors of aminoglycoside-modifying enzymes. This would allow renewal of the use of antibiotics already meeting widespread resistance and would increase the potential of a new generation of antibiotics.

The Effect of Antitumor Antibiotic Olivomycin A and Its New Semi-synthetic Derivative Olivamide on the Activity of Murine DNA Methyltransferase Dnmt3a.

Olivomycin A is a highly active antitumor drug that belongs to the family of aureolic acid antibiotics. The antitumor effect of olivomycin A is related to its ability to bind to the DNA minor groove in GC-rich regions as Mg2+-coordinated complexes. Characterization of cellular targets of olivomycin A and its mechanism of action is crucial for the successful application of this antibiotic in clinical practice and development of semi-synthetic derivatives with improved pharmacological properties. Previously, we have shown that minor groove ligands are able to disrupt the key epigenetic process of DNA methylation. In this paper, we have studied the impact of olivomycin A and its improved semi-synthetic analogue N,N-dimethylaminoethylamide of 1'-des-(2,3-dihydroxy-n-butyroyl)-1'-carboxy-olivomycin A (olivamide) on the functioning of de novo DNA methyltransferase Dnmt3a (enzyme that carries out methylation of cytosine residues in the DNA CG-sites in eukaryotic cells) using an in vitro system consisting of the murine Dnmt3a catalytic domain and a 30-mer DNA duplex containing four consecutive GC pairs. We have shown that olivomycin A and olivamide inhibit Dnmt3a with IC50 of 6 ± 1 and 7.1 ± 0.7 µM, respectively. Neither olivomycin A nor olivamide interfered with the formation of the specific enzyme-substrate complex; however, olivomycin A prevented formation of the covalent DNA-Dnmt3a intermediate that is necessary for the methylation reaction to proceed. The inhibitory effects of olivomycin A and olivamide can be explained by the disruption of the enzyme catalytic loop movement through the DNA minor groove (the reaction stage that precedes the covalent bond formation between DNA and the enzyme). The results of this work indicate the epigenetic contribution to the antitumor effect of aureolic acid group antibiotics.

Hybrid Antibiotics Based on Azithromycin and Glycopeptides: Synthesis and Antibacterial Activity.

A series of hybrid antibiotics on the basis of azithromycin and glycopeptides with the glycopeptide molecule attached via the aminoalkylcarbamoyl spacer to 11-position of the macrolide was synthesized. All the synthesized compounds demonstrated equal or superior to azithromycin and vancomycin antibacterial activity against 7 tested strains of grampositive bacteria. The new hybrid antibiotics were more active than azithromycin or vancomycin against S.pneumoniae ATCC 49619. Some of the compounds were active against E.faecium and E.faecalis strains resistant to vancomycin.

Olivomycin induces tumor cell apoptosis and suppresses p53-induced transcription.

Olivomycin (DNA-binding antibiotic) in nanomolar concentrations induces apoptosis of human tumor cells and inhibits p53-dependent transcription of the reporter gene (basal and induced by antitumor drugs). Olivomycin aglycon induces no cytotoxicity and does not block transcription.