Faced with the emergence of forms of resistance, the project proposes a new solution to kill only Streptococcus pneumoniae. It is based on the use of the Click reaction and the bacterium ability to metabolise modified metabolites with clickable functions.
Creating chemical bonds in a controlled manner in a living cell has a great potential of applications in the fields of biology and medicine but remains a major challenge. In the PneumoClick project, we will exploit click chemistry and specificities of the cell wall biosynthesis pathway in the human pathogen Streptococcus pneumoniae. Our main objective is to demonstrate that it is possible to coordinate chemical reactivity with several processes in living organism in order to control spatio-temporally the formation of covalent bonds in vivo. We will test the capacity of this innovative strategy to selectively inhibit the growth of susceptible and resistant strains of S. pneumoniae. The aim is to propose a new therapeutic solution specifically targeted against this pathogen to preserve the microbiote while limiting antibiotic resistance.
The project proposes to synthesise 'clickable' pairs between two types of metabolites. Their metabolic incorporation is to be monitored by fluorescent labelling. The kinetics of click reactions will be monitored by NMR. The antibacterial effect and selectivity for S. pneumoniae will be evaluated on wild and mutant strains
The objective of the first 18 months was to synthesize first generation compounds at Partner 1 (coordinator: Y.S. Wong), allowing us to find out whether the hypothesis of carrying out the Click reaction between key biopolymers (teichoic acid and peptidoglycan) could prevent the formation of the bacterial wall leading to an innovative antibacterial therapeutic treatment approach. We have developed new synthetic routes to functionalize our metabolites with clickable functions. These are intended to function under in vivo conditions and are known to be difficult to synthesize. It is planned to make a first kit of 4 different pairs of clickable metabolites. We were able to identify the kinetics of these clickable pairs by NMR. 80% of the synthesis objectives were achieved and allowed us to start the first trials at Partner 2 (Resp. C. Durmort). The result of these first trials was encouraging for the incorporation of new clickable metabolites for peptidoglycan. Studies are underway to attempt the cross-linking reaction between the two types of biomacromolecules. Partner 3 (resp. I. Pelloux) is waiting for the first positive results from Partner 2 before starting testing this approach on resistant strains.
In parallel, Partner 1 has also started the synthesis of new fluorogenic probes to trace both the incorporation of our metabolites and their subsequent cross-linking reaction.
A PhD student (Morgane Baudoin) was recruited on 1 October 2020 to work on the project.
The prospects are that the synthesis of the reagent pairs (2 pairs remaining) by the end of 2021. For the first half of 2022, the objective is
to finish the synthesis of the profluorophore. It is also expected that the first hits of the project's objective will be made quickly, with a view to writing a publication in 2022
The fight against bacterial resistance is a major public health issue and requires constantly finding new solutions to fight bacterial infections and stay one step ahead. The PneumoClick project aims to work on a novel antibacterial strategy that selectively targets Streptococcus pneumoniae. The therapeutic action is linked to an innovation that seeks to block growth in this pathogen by interfering with the synthesis of its bacterial wall.
The mechanism of action is original because it aims to crosslink the two main biopolymers that constitute of the bacterial wall.
From a chemical point of view, the creation of chemically controlled bonds in a living environment remains a major challenge. Its mastery will pave the way for new and innovative applications in the medical and biological fields. Our project aims to demonstrate that it is possible to coordinate chemical reactivity with a living process to control spatio-temporally the formation of covalent bonds and propose a new therapeutic solution against a bacterial pathogen. This innovative approach, which addresses a new antibacterial target, may provide a new antibiotic therapy to treat resistance problems. In addition, its selectivity for the pathogenic bacterium will avoid inducing resistance on other strains.
The success of the project is based on the expertise of a consortium of chemists, microbiologists and hospital staff, some of whom have already worked together and developed a specific method to label one of the two bacterial wall biopolymers involved in the project that had never been selectively labeled by fluorescence. This recent work has made it possible to co-label and demonstrate the concomitant biogenesis of our two biopolymers to be crosslinked, a prerequisite for our therapeutic strategy. These methods, which combine simplicity, selectivity and high spatial and temporal resolution, will allow the PneumoClick project to monitor in detail each parameter of the therapeutic action in order to optimize the molecules under the best conditions.
Monsieur Yung-sing Wong (DEPARTEMENT DE PHARMACOCHIMIE MOLECULAIRE)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Laboratoire de Bactériologie-Hygiène Hospitalière
IBS INSTITUT DE BIOLOGIE STRUCTURALE
DPM DEPARTEMENT DE PHARMACOCHIMIE MOLECULAIRE
Help of the ANR 352,088 euros
Beginning and duration of the scientific project: March 2020 - 48 Months