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Under the specter of the resurgence of pathogens due to the propagation of antimicrobial resistance (AMR) genes, innovative bacteria-killer strategies are needed. In Syngulon, we are currently developing bacteriocin-based solutions to tackle this problem and bacterial contamination in general. In a review recently published in Trends in Microbiology, we summarize the benefits of bacteriocins compared to antibiotics for personalized human applications, and we specifically emphasize their easy large-scale production and bioengineering. We also highlight how we could stimulate bacteriocin-producing bacteria of our microbiota to exploit their arsenal “on-site” and reshape endogenous bacterial populations (in collaboration with UCLouvain).
This figure from from Hols et al., 2019 highlights the four modes of bacteriocin production. In addition to the classical fermentation process, new developments in chemical synthesis allow an economically sustainable production of bacteriocins. Moreover, bacteriocins can be produced by synthetic biology techniques such as in vitro transcription-translation systems. Finally, bacteriocin-producing bacteria of our microbiota might be stimulated to secrete bacteriocins and treat gut infection.
This figure also depicts the bioflexibility of natural bacteriocins that might be engineered to provide variant molecules with more interesting properties. For instance, next-generation bacteriocins could be developed that are more resistant to proteases, are more efficient, possess a different prey spectrum, or could be a chimera of several bacteriocins.
Bacteriocins are known to play a role in bacterial communication and ecology. For example, the gut and oral cavity are parts of the human body that accommodate thousands of different bacterial species. These bacteria, often beneficial for human health, are continuously in a stressful environment and compete for food and space. When he was researcher in Prof. Pascal Hols lab (UCL/LIBST), Dr. Johann Mignolet (now R&D Project Manager of Syngulon) demonstrated that Streptococcus salivarius, a commensal human gut bacterium, uses a communication pheromone to concomitantly trigger two responses: the ability to modify its genome via the acquisition of “foreign” DNA and the production of potent bacteriocins. These toxins or non-transformable variants of S. Salivarius could be used for medical purposes to kill harmful multi-resistant superbugs such as Staphylococcus aureus and several streptococci.
This figure adapted from Mignolet et al, 2018, shows the different transcriptional cascades that trigger competence entry and expression of bacteriocin–encoding genes in four different streptococci models: S. salivarius, S. thermophilus, S. mutans and pneumoniae. Specifically interesting is that the BlpRH/BlpC bacteriocin regulatory system is missing or incomplete in S. Salivarius. The boxes show systems shared between species. Large continuous arrows depict transcriptional control, and dashed arrows display protein translation. Small continuous arrows indicate protein/peptide/phosphate motion.
The bacterium-killing assay below demonstrates addition of a pheromone inducing bacteriocin production, which leads to an inhibitory effect on surrounding bacteria.