Aminoalkylamides of Eremomycin Exhibit an Improved Antibacterial Activity.

Elena I Moiseenko,Elena P Mirchink,Elena B Isakova,Gyula Batta,Natalia E Grammatikova,Réka Erdei,Eleonora R Pereverzeva,Andrey E Shchekotikhin

doi:10.3390/ph14040379

Abstract

After decades, the glycopeptide vancomycin is still the preferred antibiotic against resistant strains of Gram-positive bacteria. Although its clinical use is strictly regulated, the gradual spread of vancomycin-resistant bacteria, such as glycopeptide-resistant and glycopeptide-intermediate Staphylococcus aureus and vancomycin-resistant Enterococcus spp., is a serious health problem. Based on the literature data and previous studies, our main goal was to assess the antimicrobial potential and to study the structure–activity relationship of new eremomycin aminoalkylamides. We designed and synthesized a series of new eremomycin amides in which eremomycin is conjugated with a hydrophobic arylalkyl group via an alkylenediamine spacer, and tested their antibacterial activities on a panel of Gram-positive strains that were sensitive and resistant to a “gold-standard” vancomycin. Based on the data obtained, the structure–activity relationships were investigated, and a lead compound was selected for in-depth testing. Research carried out using an in vivo model of staphylococcus sepsis, acute toxicity studies, and the estimated therapeutic index also showed the advantage of the selected eremomycin amide derivative in particular, as well as the chosen direction in general.

Highlights

The derivatives obtained in aobtained good yield good yield of 47–67%, and their general synthesis scheme are shown in reaction was their general structure and structure synthesisand scheme are shown in Scheme
Comparing the activities of the new derivatives, it can be noted that the potency against resistant strains of enterococci followed the same pattern as the activity against sensitive strains of Gram-positive bacteria—derivatives containing fluorine as a substituent in benzyl showed a slightly higher activity than chlorine-containing congeners
In the course of this work, we prepared and characterized 17 new eremomycin amides in which eremomycin was conjugated with an aromatic ring of substituted benzyl via diamine residue

Summary

Introduction

The glycopeptide antibiotics (Figure 1) vancomycin (1) and teicoplanin (2) are used for the treatment of infections caused by MRSA, as well as penicillin-resistant strains of S. pneumoniae and C. difficile [3]. Resistance to glycopeptide antibiotics has been developing for a long time, at present, it is a rather serious problem. Resistant strains, such as vancomycin-resistant enterococci (VRE), glycopeptide-resistant enterococci (GRE), and glycopeptide-resistant and glycopeptide-intermediate S. aureus (GISA), call into question the further use of vancomycin and even other glycopeptide antibiotics [4,5,6]

Methods

Results

Discussion

Conclusion