Soutenance publique de thèse de doctorat en Sciences chimiques - Arnaud BEAUFAYS

Synthesis of beta-lactams for the electrochemical detection of bacterial antibioresistance

Jury

• Prof. Steve LANNERS (département de chimie, UNamur), président
• Prof. Stéphane VINCENT (département de chimie, UNamur), promoteur et secrétaire
• Prof. Jean-Christophe MONBALIU (département de chimie, ULiège)
  
• Prof. Raphaël ROBIETTE (Molecular Chemistry, Materials and Catalysis, UCLouvain)
  
• Dr Pascal MERTENS (Entreprise Coris BioConcept)
  

Résumé

In the past decades, bacteria have acquired more and more resistances to antibiotics and in 2018 the World Health Organization declared: “Without urgent action, we are heading for a post antibiotic era, in which common infections and minor injuries will once again kill”. When the common resistance mechanisms are considered, the most powerful antibiotics are inefficient against some multi-resistant bacteria already today. Among all resistance mechanisms, we focused on the production of beta-lactamases, which are enzymes that have the ability to cleave the beta-lactam ring of antibiotics, and so make them inefficient. The detection of antimicrobial resistance is crucial in hospitals and other medical structures to provide fast and efficient treatment to patients.

Recently, a cephalosporin analogue that was employed in colorimetric assays, was found to be also able to detect the presence of beta-lactamases by an electrochemical reaction. Therefore, in partnership with Coris BioConcept, a company developing diagnostic tools, we decided to develop a new generation of cephalosporins designed to provide an optimal electrochemical beta-lactamase detection.

In this PhD, we first focused on the total synthesis of this molecule from two different starting materials, which to the best of our knowledge, has never been thoroughly described in the literature. Then, structural modifications were performed to study both the impact on the electrochemical response and the stability of the molecule. In parallel, other structural modifications were performed to study the impact on enzyme selectivity. The objective of these modifications is to achieve a complete selectivity for carbapenemases, which are among the high-concern beta-lactamases.

In the last section, we attempted to answer a fundamental question: what is the product generated after the electrochemical reaction? The proposed mechanism is supported by computational studies and a rationalisation of the results obtained in the other chapters.

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