Mathias Schmelcher

Zurich University of Applied Sciences (ZHAW)

Institute of Chemistry and Biotechnology

PD Dr. Mathias Schmelcher is a leading researcher in enzyme-based antimicrobial agents, specializing in bacteriophage-derived lysins for combating antibiotic-resistant bacteria. As the Head of Molecular Biology and Biochemistry at ZHAW School of Life Sciences and Facility Management, he co-leads research efforts focusing on the application of phage-derived proteins in medical and biotechnological contexts.

Authors: Röhrig C1, Keller AP1, Sobieraj A1, Huemer M2, Chang CC2, Mairpady Shambat S2, Keller N2, Phothaworn P3, Blanco Massani M4, Zinsli L1, Meile S1, Eichenseher F1, Shen Y1, Bernkop-Schnürch A4, Korbsrisate S3, Zinkernagel AS2, Loessner MJ1, Schmelcher M1, 5

Affiliations: (1). Institute of Food, Nutrition and Health, ETH Zurich, Zurich (Switzerland) (2). Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich (Switzerland) (3). Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok (Thailand) (4). Centre for Chemistry and Biomedicine (CCB), Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innsbruck (Austria) (5). Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences (ZHAW), Wädenswil, Zurich (Switzerland)

In the light of the current antimicrobial resistance crisis, bacteriophage endolysins have gained increasing attention as a promising class of antibacterial agents, due to their strong bactericidal activity, high specificity for their target bacteria, activity against biofilms, persister cells, and drug-resistant strains, and their low probability of resistance development. Owing to their modular architecture, endolysins and other peptidoglycan hydrolases (PGHs) can readily be engineered to create protein chimeras with novel properties. Our lab has compiled a large collection of engineered staphylococcal PGHs, which can be rapidly screened for candidates featuring desired characteristics with respect to potential therapeutic applications, such as high activity against staphylococci in human serum or intracellular environments. Despite the aforementioned advantages, systemic administration of PGHs is currently hampered by several factors such as a lack of cell-penetrating properties, insufficient accumulation at infection sites, short circulation half-lives, and immunogenicity. In order to tackle such hurdles, we further modify our pre-selected chimeric PGHs, e.g., by fusion to various functional peptides. PGHs equipped with cell-penetrating peptides (CPPs) effectively reduced intracellular staphylococci, both in vitro and in vivo; cell-penetrating homing peptides (CPHPs) were able to specifically direct PGHs to bone cells and significantly reduce S. aureus in a murine bone infection model; and fusion of PGHs to an albumin binding domain increased their circulation half-life and, consequently, their therapeutic efficacy. Taken together, such improvements could bring PGHs one step closer to the clinic.