Discovering the Potentials of Four Phage Endolysins to Combat Gram-Negative Infections.

Aleksei I Laishevtsev,Victoria S Yakimakha,Daria V Vasina,Evgeny V Usachev,Timofey A Remizov,М А Никифорова ,В Д Потапов ,В Н Макаров ,S M Yudin ,Igor V Grigoriev,Anastasiya M Lendel,Andrei A Pochtovyi,В.а Гущин ,Aleksei M Vorobev,А В Алешкин ,Mikhail V Fursov,N V Shevlyagina ,V G Zhukhovitsky ,N D Antonova ,Artem P Tkachuk

doi:10.3389/fmicb.2021.748718

Abstract

Endolysin-based therapeutics are promising antibacterial agents and can successfully supplement the existing antibacterial drugs array. It is specifically important in the case of Gram-negative pathogens, e.g., ESKAPE group bacteria, which includes Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species, and are highly inclined to gain multiple antibiotic resistance. Despite numerous works devoted to the screening of new lytic enzymes and investigations of their biochemical properties, there are significant breaches in some aspects of their operating characteristics, including safety issues of endolysin use. Here, we provide a comprehensive study of the antimicrobial efficacy aspects of four Gram-negative bacteria-targeting endolysins LysAm24, LysAp22, LysECD7, and LysSi3, their in vitro and in vivo activity, and their biological safety. These endolysins possess a wide spectrum of action, are active against planktonic bacteria and bacterial biofilms, and are effective in wound and burn skin infection animal models. In terms of safety, these enzymes do not contribute to the development of short-term resistance, are not cytotoxic, and do not significantly affect the normal intestinal microflora in vivo. Our results provide a confident base for the development of effective and safe candidate dosage forms for the treatment of local and systemic infections caused by Gram-negative bacterial species.

Highlights

The rapid increase of the discovery of new antibiotics during the 1950–60s is replaced with moderate development of these therapeutics because of the growing commercial risks associated with the emergence of bacterial resistance
Very few of the studies are devoted to in vivo application and just several molecules are in clinical trials (Abdelrahman et al, 2021; Grabowski et al, 2021; Schmelcher and Loessner, 2021). Such a trend does not promote the acceleration of the development and implication of endolysinbased drugs into clinical practice. It remains unclear what is the potential of using these molecules, especially for the treatment of drug-resistant Gram-negative bacteria-induced infections, which are the limitations and advantages of endolysin administration as individual antimicrobial therapy or in combination with antibiotics
We provide a comprehensive study of four different unmodified Gram-negative bacteria-targeting endolysins, LysAm24, LysAp22, LysECD7, and LysSi3, devoted to their in vitro and in vivo potentials

Summary

Introduction

The rapid increase of the discovery of new antibiotics during the 1950–60s is replaced with moderate development of these therapeutics because of the growing commercial risks associated with the emergence of bacterial resistance. This has resulted in a rising focus on the development of derivatives of known antibiotics rather than discovery of antimicrobials with fundamentally new mechanisms of action. An active search for nonconventional approaches to limit or eliminate the emergence of resistant infectious agents’ burden is carried out (Theuretzbacher et al, 2020). This resembles a classical and effective mechanism of action of several classes of antibiotic agents (glycopeptide antibiotics, β-lactams, and polymyxins); on the other hand, it is believed that the enzybiotic mechanism of action oriented toward specific conservative targets will lead to the less dramatic and slow emergence of bacterial resistance (Grishin et al, 2020)

Methods

Results

Conclusion