All-in-one supramolecular approach as an innovative anti-infectious strategy

Introduction

Despite the large therapeutic arsenal available to fight bacterial infections, the development of new anti-infectious strategies is a major public health concern. Pathogens have indeed developed a variety of Multi Drug Resistance mechanisms to escape destruction.

Proposed Alternatives

To circumvent these problems, a few promising alternatives have been proposed:

1. Bacterial Adhesion Inhibition
   A first approach focuses on the bacterial adhesion step to the host cells, which involves multivalent interactions between the glycocalyx and bacterial adhesins. Molecular constructs displaying clusters of carbohydrates have been shown to efficiently compete with these complex recognition processes, thus having the potential to prevent this key step of the bacterial infection.

2. Natural Antibody Recruitment
   The recruitment of natural antibodies (NAbs) present in the human bloodstream against biological targets to stimulate their destruction by the immune system is another alternative to fight pathogens. This approach is based on the utilization of bimodal molecules (namely ARGs, Antibody Recruiting Glycodendrimers) which are composed of two recognition domains: one for NAbs and one for receptors expressed by the pathogen.

Previous Demonstrations

The potential of this "recruiting strategy" was demonstrated recently in the PI's team in the context of cancers, where NAbs have been efficiently redirected against tumors (ERC CoG LEGO and ERC PoC THERA-LEGO).

Project Overview

For the first time, PATHO-LEGO will take advantage of these two "antiadhesive" and "recruitment" strategies simultaneously to fight resistant strains of Pseudomonas aeruginosa.

Objectives

We aim at developing hybrid ARGs that will:

• Block extracellular processes that P. aeruginosa uses to infect host cells.
• Redirect NAbs against the bacteria to induce their immune-mediated clearance.

With this unprecedented approach, we will be able to both prevent infection and kill the targeted resistant bacteria to optimize the antibacterial effect.