Combination Effect of Engineered Endolysin EC340 With Antibiotics.

Hye-Won Hong,Min Soo Kim,Heejoon Myung,Young Deuk Kim,Jaeyeon Jang,Miryoung Song

doi:10.3389/fmicb.2022.821936

Hye-Won Hong, Min Soo Kim + Show 4 more

Open Access

https://doi.org/10.3389/fmicb.2022.821936

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Abstract

Bacteriophage lysins, also known as endolysins or murein hydrolases, are hydrolytic enzymes produced by bacteriophages during the final stage of the lytic cycle to enable cleavage through the host’s cell wall, thus allowing the phages to burst out of their host bacteria after multiplication inside them. When applied externally to Gram-negative bacteria as recombinant proteins, lysins cannot easily reach the cell wall due to the presence of an outer membrane (OM). In this study, endolysin EC340 obtained from phage PBEC131 infecting Escherichia coli was engineered for improved OM permeability and increased activity against Gram-negative bacteria. The engineered endolysin, LNT113, was tested for potential synergistic effects with standard-of-care antibiotics. A synergistic effect was demonstrated with colistin, while an additive effect was seen with meropenem, tigecycline, chloramphenicol, azithromycin, and ciprofloxacin. Neither ceftazidime nor kanamycin showed any synergy or additive effects with the LNT113 endolysin. Moreover, synergy and additive effects could not be generalized by antibiotic class, OM traverse mechanism, molecular weight, or the bactericidal nature of each antibiotic tested.

Highlights

The increase in multidrug-resistant (MDR) bacteria poses a major threat to morbidity and mortality worldwide
In the late life cycle of phages, holin, a small membrane protein, forms pores in the bacterial cytoplasmic membrane, and when endolysin produced in the cytosol reaches this peptidoglycan layer, cell lysis results (Wang et al, 2000)
Unlike with Gram-positive bacteria, in which the peptidoglycan cell wall is exposed, most extracellular endolysins are limited in their ability to degrade peptidoglycan due to the presence of an outer

Summary

Introduction

The increase in multidrug-resistant (MDR) bacteria poses a major threat to morbidity and mortality worldwide. In the late life cycle of phages, holin, a small membrane protein, forms pores in the bacterial cytoplasmic membrane, and when endolysin produced in the cytosol reaches this peptidoglycan layer, cell lysis results (Wang et al, 2000). Due to this enzymatic activity, endolysins with potential antibacterial activities have been reported (Schmelcher et al, 2012). Unlike with Gram-positive bacteria, in which the peptidoglycan cell wall is exposed, most extracellular endolysins are limited in their ability to degrade peptidoglycan due to the presence of an outer

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