Evaluation of New Antimicrobial Agents Based on tris(1H-Indol-3-yl)methylium Salts: Activity, Toxicity, Suppression of Experimental Sepsis in Mice.

Alexey S Trenin,Vasilisa A Polozkova,Sergey N Lavrenov,Michael I Treshchalin,Alexander Y Simonov,Victor V Tatarskiy,Elena B Isakova,Alexey A Panov,Elena P Mirchink,Olga P Bychkova

doi:10.3390/ph15020118

Abstract

The antimicrobial activity and toxicity of three novel synthetic antibacterial agents containing tris(1H-indol-3-yl)methylium fragment were studied in vitro and in vivo. All compounds in vitro revealed high activity (minimal inhibitory concentration (MIC) 0.13–1.0 µg/mL) against bacteria that were either sensitive or resistant to antibiotics, including multidrug-resistant clinical isolates. The derivatives combining high antimicrobial activity with relatively low cytotoxicity against human donor fibroblasts HPF-hTERT were subjected to further testing on mice. In vivo they revealed fairly good tolerance and relatively low toxicity. Acute toxicity was evaluated, and the main indicators of toxicity, including LD50 and LD10, were determined. A study of compounds in vivo showed their efficiency in the model of staphylococcal sepsis in mice. The efficiency of compounds may be due to the ability of indolylmethylium salts to form pores in the cytoplasmic membrane of microbial cells and thereby facilitate the penetration of molecules into the pathogen.

Highlights

Received: 13 December 2021Recently, compounds containing aryldi(indolyl)methyl or tris(indolyl)methyl fragments have attracted the interest of researchers
We propose to try and prevent the drug resistance by the rational use of antibiotics and by development of new antimicrobial agents capable of overcoming drug resistance [14]
We obtained a series of symmetric N-alkyl-substituted tris(indolyl)methylium salts possessing significant antibacterial and antifungal activity [15]

Summary

Introduction

Received: 13 December 2021Recently, compounds containing aryldi(indolyl)methyl or tris(indolyl)methyl fragments have attracted the interest of researchers. The situation in the field of therapy of infectious diseases has been significantly complicated due to the wide spread of pathogens resistant to known antibiotic drugs [11,12,13]. To solve this problem, we propose to try and prevent the drug resistance by the rational use of antibiotics and by development of new antimicrobial agents capable of overcoming drug resistance [14]. We obtained a series of symmetric N-alkyl-substituted tris(indolyl)methylium salts possessing significant antibacterial and antifungal activity [15]

Methods

Findings

Discussion

Conclusion