Fragment-based Inhibitors and Irreversible inhibitors of the Bacterial REplication – FIIBRE

FIIBRE is a multidisciplinary project that will develop and validate a new class of antibiotics, targeting in priority ESKAPE and multi-resistant bacterial strains in order to limit the emergence and spreading of new resistances. This original therapeutic exploits a new molecular target, never exploited yet : the bacterial replication ring (or sliding clamp, SC). This highly conserved replicase core protein controls access to the replication fork of all DNA polymerases which interact, via a short conserved peptidic motif, in a hydrophobic pocket located on the SC surface. These interactions are essential to their functions and their inhibition lead to replication arrest and cell death. Such inhibitions also block DNA transaction processes that contributes to adaptation and to the development of antibiotic resistance. We have previously developed antimicrobial peptides that interact with SC with high affinity, inhibit bacterial replication, show bactericidal activity in ESKAPE and MDR strains and improve the survival of Drosophila infected with E. coli. Because therapeutic peptides frequently faces the problems of delivery and in vivo stability, we will also search for small non-peptidic molecules which could combine good membrane permeation in bacteria and in vivo stability.
Our consortium, which includes chemoinformatics specialists (P2), chemists (P3), biochemists, biophysicists and microbiologists (P1, P4), will develop small molecules targeting the SC hydrophobic pocket. We will build on our knowledge of the SC/peptide system and our recent data from 1- a fragments screening campaign and 2- covalent peptides development, to design, synthesize, optimize and test in vitro and in vivo new small molecules able to penetrate bacteria and having an antibiotic activity through irreversible engagement of SC. The best candidates will then enter into a valuation process.