Periodic Reporting for period 2 - CAPSID (Controlling Activity of Lysogenic Phages by Small Molecule Inducers and Dysregulators)
Reporting period: 2022-04-01 to 2023-09-30
The human body is host to an enormous number and diversity of microorganisms. These microorganisms play crucial roles in our body's functions and even how diseases develop. Interestingly, microorganisms have their own natural enemies, which are viruses. Some of these viruses specifically attack bacteria and are called phages. Phages can exist in two different states: while lytic phages actively take over and destroy bacteria, lysogenic phages stay in a quiet and hidden state called prophages, where they become a part of the bacterial cell's genetic blueprint. As the bacteria grow and divide, these prophages are copied and passed along to the new cells. Surprisingly, this process can actually benefit the bacterial population by helping them adapt and survive. But there's a twist! Under certain circumstances, these silent prophages can suddenly wake up and become active. When this happens, they take over the bacterial cell's machinery and start making new virus particles. As a result, the bacterial cell is destroyed, and the newly made viruses go on to infect other healthy cells. In our ERC Consolidator Project CAPSID our team is delving into understanding what controls this transition of phages from their silent, lysogenic state to an active, lytic one. We are curious to find out which chemical substances are involved in this process and if microbial metabolites are capable of inducing prophages in their competitors. We also aim to develop customized small molecules that allow us to selectively control prophage activity. Investigating metabolites involved in prophage induction will give us a better understanding of the chemistry of competitive interactions of bacteria in the human microbiome. Exploiting these metabolites by chemical synthesis and developing customized compounds to control prophage activity will yield important tools for research and may even lead to new ways of tackling bacterial infections, maybe even finding alternatives to antibiotics.
We have screened a large variety of bacterial species and strains of the human microbiome for mutual prophage induction and elucidated the chemical structure of active metabolites. We hereby discovered one compound, pyochelin, which is produced by the bacterium Pseudomonas aeruginosa and triggers the conversion of a prophage, residing in a strain of the species Staphylococcus aureus, from a silent companion into a deadly parasite. Our study also shows that a chemical trigger of prophage induction can exhibit selectivity on species and even phage level. We have also made major steps to unveil the mode of action of pyochelin by biochemical investigations into its mechanism within the cell.
The discovery of pyochelin as species- and prophage selective inducer demonstrates the first known case of microbial interactions between species mediated by prophage inducers. Our study also provides the first evidence that chemical signaling agents can exhibit selectivity for specific phages in a polylysogenic bacterial host strain. We will further elucidate the molecular basis for this unprecedented selectivity and investigate if there are other molecules with prophage inducing activities.