Research

BREAKthrough is breaking the barrier

An integrated multidisciplinary approach to kill Gram-negative bacteria through existing antibiotics by making their outer membrane permeable

No novel antibacterial drug classes have been discovered and developed for clinical use since 1987. This lack of innovation in antimicrobial research has resulted in limited new options to address multi-drug-resistant bacteria like Gram-negative (Gram-) bacteria. Infections by multi-drug-resistant Gram- bacteria are particularly hard to treat because the impermeability of the outer membrane restricts access by existing standard-of-care antibiotics. The goal of the BREAKthrough project is, therefore, to destabilise the outer membrane and make it permeable, sensitising the Gram- bacteria to antibiotics.

BREAKthrough aims to sensitise bacteria towards new and existing drugs.

Prof. Jean-François Collet

UCLouvain, BREAKthrough coordinator

To make multi-drug-resistant Gram- bacteria vulnerable to standard-of-care antibiotics, their outer membrane, their barrier to the outer world, needs to be broken. For this purpose, the project will target three key protein systems that are essential to maintain the outer membrane. Defects in any of these three targets have been shown to increase the permeability of the outer membrane, allowing a large variety of drugs to enter the cell. BREAKthrough aims to deliver molecules that inhibit these three protein machineries.

More specifically, the BREAKthrough project aims to achieve the following objectives:

Develop and optimise specific bacterial assays that report on defects in Bam and Lpt multicomponent machineries and in L,D-Transpeptidases, as well as use and optimise recently developed screening assays that report on OM stress and permeabilisation. Existing and newly synthesised libraries provided by the industrial collaborators will be tested, and this may lead to the repurposing of existing drugs.
Develop an in vivo screening assay for compounds that permeabilise the OM using a zebrafish infection model that reports on sensitisation to large-scaffold antibiotics.
Construct an open-access BREAKthrough data hub that defines the physicochemical characteristics of compounds that can cross the OM of GNB based on an SPPR that is to be defined. The purpose of the database is to facilitate a rational drug design.
Optimise lead compounds in iterative synthesis/testing rounds based on SPPR findings.