Abstract:
While bacteriophages offer great host specificity and killing activity, their therapeutic potential is naturally limited by narrow host-ranges, insufficient antimicrobial activity, lysogeny, and rapid emergence of resistance. However, there are several ways to overcome these limitations and provide smart and effective phage-based antimicrobials [1].
We engineered bacteriophages based on in-vitro DNA assembly and subsequent reactivation of synthetic phage genomes within suitable host cells. For efficient rebooting of viral genomes in Gram-positive bacteria, we use a bacterial L-form based platform, providing cross-genus surrogate hosts for phage amplification. To enhance recombination-based engineering of very large phage genomes unsuitable for synthetic assembly, CRISPR-Cas systems were established in various phage hosts.
Based on a broad selection of phages infecting important pathogens such as E. coli, Klebsiella, Staphylococcus, Enterococcus, and Listeria, it was possible to (i) convert temperate phages to virulent ones, (ii) produce phages carrying a broad variety of additional payload genes for enhanced self- or cross killing activity [2], (iii) broaden phage host ranges by structure-guided design, and (iv) provide a corresponding arsenal of nano-luciferase reporter phages as companion diagnostics for use in clinical phage therapy [3].
Besides using functional bacteriophages, another successful approach is to harness the bacteriolytic function of phages, i.e., the endolysins. Here, we have made significant progress by not only optimizing enzyme activity and in vivo half-life by domain shuffling and fusion to non-phage sequence, but also modification of the enzymes for fine-tuned application in serum and blood, tissue, and intracellular environments [4].

Bio:
Martin Loessner studied Biology at the University of Freiburg in Germany and Wayne State University in Michigan, USA, and earned his PhD from the Technical University of Munich. Since 2003, he has served as a Professor of Microbiology in the Department of Health Science and Technology at ETH Zurich, Switzerland.
A leading expert in microbiology, Martin Loessner has dedicated his career to studying the bacterial cell wall and bacteriophages, with a focus on pathogens such as Listeria and Staphylococcus. He has been a pioneer in developing phage-based technologies for food safety, diagnostics, and therapeutic applications. His groundbreaking work on phage engineering has contributed to the advancement of phage therapy as a promising alternative to antibiotics and has earned widespread recognition for translation of fundamental research into innovative, real-world solutions.