Recombinant Endolysins as Potential Therapeutics against Antibiotic-Resistant Staphylococcus aureus: Current Status of Research and Novel Delivery Strategies

Abstract

is one of the most common pathogens of humans and animals, where it frequently colonizes skin and mucosal membranes. It is of major clinical importance as a nosocomial pathogen and causative agent of a wide array of diseases. Multidrug-resistant strains have become increasingly prevalent and represent a leading cause of morbidity and mortality. For this reason, novel strategies to combat multidrug-resistant pathogens are urgently needed. Bacteriophage-derived enzymes, so-called endolysins, and other peptidoglycan hydrolases with the ability to disrupt cell walls represent possible alternatives to conventional antibiotics. These lytic enzymes confer a high degree of host specificity and could potentially replace or be utilized in combination with antibiotics, with the aim to specifically treat infections caused by Gram-positive drug-resistant bacterial pathogens such as methicillin-resistant . LysK is one of the best-characterized endolysins with activity against multiple staphylococcal species. Various approaches to further enhance the antibacterial efficacy and applicability of endolysins have been demonstrated. These approaches include the construction of recombinant endolysin derivatives and the development of novel delivery strategies for various applications, such as the production of endolysins in lactic acid bacteria and their conjugation to nanoparticles. These novel strategies are a major focus of this review.

The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-ResistantStaphylococcus aureusBacteriolysis

“…Extension to other lysins. CF-301 was originally identified as a Streptococcus suis prophage lysin exhibiting a domain arrangement commonly observed in many antistaphylococcal lysins (5,56) and defined by a catalytic N-terminal cysteine-histidinedependent amidohydrolase/peptidase (CHAP) domain linked to a cell wall-binding C-terminal domain belonging to the SH3b family of proteins (57,58). We predicted that lysins of this group, which include enzymes active against both staphylococci and streptococci (like CF-301), as well as enzymes active against only staphylococci (59), would all exhibit the CF-301-like potentiation effect in human blood.…”

ClyJ Is a Novel Pneumococcal Chimeric Lysin with a Cysteine- and Histidine-Dependent Amidohydrolase/Peptidase Catalytic Domain

“…Adding purified lysins exogenously to susceptible Gram-positive bacteria can cause rapid cell lysis. Due to their high specificity and robust lytic activity, lysins offer an alternative antimicrobial approach to conventional antibiotics (10,11). Currently, several lysins targeting Staphylococcus aureus have progressed to human clinical trials, such as the natural lysin CF-301 (https://clinicaltrials.gov/ct2/ show/NCT03163446#wrapper) and the chimeric lysin P128 (https://www.clinicaltrials .gov/ct2/show/NCT01746654?termNCT01746654&rank1).…”

Future topical medications in chronic rhinosinusitis

“…Although Felix d'Herelle described the first successful bacteriophage delivery over a century ago, the use of phages declined abruptly due to the discovery of antibiotics. As a consequence of the Second World War, they were quickly reduced to only being used in Eastern countries, which had no access to antibiotics . In the Western world, the emergence of multidrug‐resistant bacteria has prompted a renewed interest in alternatives to conventional antimicrobial agents.…”