When the Noble Prize-winning Alexandre Fleming discovered antibiotics, he already noticed that microorganisms developed resistance mechanisms to survive. Therefore, he anticipated that a misuse of antimicrobial compounds to treat infections will drive the selection of hyper-resistant strains and the resurgence of almost-eradicated infectious diseases. Nowadays, the problem is so critical that the World Health Organization foresees that superbugs will outcompete cancer and cardiovascular diseases to become the first cause of mortality on the planet in less than 30 years (horizon 2050). Recently, the international organization drew a list of 10 priority pathogens that includes Streptococcus pneumoniae, a bacterium notorious in pneumonia (major upper respiratory tract infections), endocarditis, meningitis and brain abscess. To replace or restore antibiotic action, we thus need to find alternative strategies. In this proposal, I aim to use bacteriocins, small antimicrobial peptides secreted by bacteria, to kill S. pneumoniae. They are currently underexploited for human need but feature many valuable characteristics (e.g. efficiency, evolvability, specific spectrum, cheap/easy production, high sequence diversity, stability) complementary to antibiotics. I will test a collection of hundreds of bacteriocins and, according to their mode of action, will rationally assemble “overwhelming” bacteriocin cocktails to prevent emergence of resistance. In parallel, a tantalizing idea would be to exploit the beneficial bacteria of our microbiota and mobilize their bacteriocins to treat local infections. So, I will perform ex vivo infection of human epithelia with S. pneumoniae and test how bacteriocin-induced S. salivarius, a commensal bacterium of our gut, influences it. Besides generating valuable fundamental insight into the S. pneumoniae resistance mechanisms and infection cycle, the results of this project will also pave the way to fight against other notorious pathogens.
