Plant-based endolysins for the treatment of multi-resistant bacterial infections

The increasing spread of multi-resistant pathogens represents one of the greatest global challenges to public health. In particular, the so-called ESKAPE bacterial pathogens pose a major problem, as they can no longer be treated with conventional antibiotics and lead to severe or even fatal illnesses, necessitating the urgent development of new therapeutic approaches. Phages, naturally occurring viruses that specifically infect and destroy bacteria, are considered a promising alternative because bacterial resistance mechanisms are ineffective against them. However, their narrow host specificity severely limits their use, and their application also carries certain safety risks. Therefore, endolysins, produced by phages, which enable them to break down bacterial cell walls, are increasingly becoming the focus of research. Endolysins are simple enzymes that, as such, have a broader spectrum of activity and, moreover, can be specifically adapted to certain bacteria due to their mechanism of action. Their use is currently hampered by the lack of suitable production methods for endolysins. Classical biotechnological production organisms such as mammalian and yeast cells cannot be used because they degrade the endolysins, while bacteria, although capable of producing them, are themselves destroyed by the endolysins. Plants, with their chloroplasts, offer a promising approach here. Chloroplasts provide the bacterial environment necessary for endolysin biosynthesis, but lack a cell wall and are therefore not attacked by the endolysins, as initial studies have successfully demonstrated.

ELYDIA's goal is therefore twofold: firstly, to establish a platform for the systematic development and adaptation of endolysins, and secondly, to create a scalable, plant-based production system that can provide sufficient quantities of endolysins to produce highly effective enzymes cost-effectively.

ELYDIA pursues a holistic approach: Using modern AI methods, (i) large metagenomic datasets are searched for suitable endolysin candidates and compiled in a database (MetaLysin), (ii) the enzymatic domains of these endolysins are systematically combined (SyntheticEvolution), and (iii) the individual domains themselves are optimized (RationalDesign) to specifically enhance their activity. The new endolysins are then produced in the chloroplasts of plants, since, as described above, they are not degraded within these chloroplasts and do not damage them. Furthermore, the large number of chloroplasts present in plant cells in the leaves (up to 100 per cell) allows for extremely high production volumes, comparable to those of classic biopharmaceutical production organisms such as mammalian and yeast cells or bacteria. Subsequently, the production and purification of these chlorolysins will be scaled up to pilot scale, and efficacy and safety will be investigated in preclinical, animal-free studies using the greater wax moth.

This project combines the complementary strengths of leading research institutions within the Max Planck Society and the Fraunhofer Society. The Fraunhofer Institute for Molecular Biology and Applied Ecology IME (FhI-IME) contributes its biotechnological expertise in protein design and engineering for the development and optimization of novel endolysins and the production of test material for (pre-)clinical studies, while the Max Planck Institute of Molecular Plant Physiology (MPI-MP) contributes its expertise in chloroplast-based plant biotechnology and high-performance production systems. This is complemented by the Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB (FhI-IGB) with its experience in the preclinical, animal-free testing of phage therapies for combating ESKAPE pathogens.

With this unique combination of state-of-the-art AI-supported drug discovery, innovative plant biotechnology, and animal-free preclinical research, ELYDIA is creating a powerful development and production platform that can contribute to the fight against antibiotic-resistant infections.