DS04 - Vie, santé et bien-être

Development of inhibitors specific of cell wall synthesis in mycobacteria – MYCWall

Submission summary

Tuberculosis is the second infectious disease leading to mortality after AIDS and one of the top ten causes of death worldwide. The emergence of multidrug-resistant strains had complicated the management of tuberculosis and constitutes a serious threat for the control of the pandemic. Drugs of the ß-lactam family have regained interest for the treatment of tuberculosis since the ß-lactamase produced by Mycobacterium tuberculosis (BlaC) is irreversibly inactivated by clavulanate. The targets of ß-lactams are unusual in M. tuberculosis since the cross-linking step of cell wall peptidoglycan synthesis is performed by L,D-transpeptidases (LDTs) instead of the classical D,D-transpeptidases belonging to the penicillin-binding protein (PBP) family. ß-lactams of the carbapenem class, such as meropenem, are active against M. tuberculosis LDTs and this drug has recently shown efficacy in combination with clavulanate in a phase II clinical trial. However, there are several limitations to the use of carbapenems for the treatment of tuberculosis including their broad antibacterial spectra, which result in adverse effects on the commensal flora, leading to opportunistic fungal infections and selection of broad-spectrum ß-lactamases in the enterobacteria. Mycobacterium abscessus, a fast growing mycobacterium, raises distinct medical issues. This bacterium has emerged in recent years as an important opportunistic pathogen increasingly responsible for mortality in cystic fibrosis patients and in the context of chronic obstructive pulmonary diseases. The carbapenem imipenem is part of the recommended treatment of lung infections due to M. abscessus but the efficacy of this drug is limited by a broad ß-lactamase (BlaMab), which is not inhibited by clavulanate. As for M. tuberculosis, the peptidoglycan of M. abscessus is mainly cross-linked by LDTs. In this context, we propose to develop new inhibitors of LDTs that will address the issues raised by carbapenems since they will be specific of LDTs, and for this reason devoid of antibacterial activity against non-mycobacterial pathogens. These new inhibitors will also be resistant to hydrolysis by the ß-lactamase BlaMab and BlaC in order to avoid the need for the association with a ß-lactamase inhibitor. In the proposal, we report the total synthesis of a new molecule active on LDTs, which cannot be described in the present publically-available summary since we haven’t yet protected our innovation. We also describe three synthetic routes for easy functionalization of the scaffold of this molecule to obtain a first series with chemical diversity. We want also to develop a second series of molecules, containing modifications of the central scaffold, by using recent synthetic methodologies. In the MYCWall consortium, the compounds obtained in the chemical Task (Partner 2, Task 1) will be used to decipher the mechanism of inactivation of LDTs by our molecules (Partner 1, Task 2). Assays will be designed to compare the efficacy of LDT inactivation by our various synthetic inhibitors. This approach will be used to identify inhibitors with the best inhibition kinetic properties. We will also check that the compounds are not inactivated by the ß-lactamase BlaC and BlaMab, as this is the case for the parental compound that we have already obtained. To assist in the rational design of the inhibitors, the compounds will be co-crystallized with model LDTs (Partner 3, Task 3). The antibacterial activity of our synthetic inhibitors will be assayed in vitro against M. tuberculosis and M. abscessus and in vivo in human macrophages infected by these bacteria. The project will enable several rounds of synthesis and biological evaluation to obtain optimized candidate leads that will be active on mycobacteria but not enterobacteria. The MYCWall project will contribute to the development of new therapies for multi-drug resistant tuberculosis and for the management of lung infections due to M. abscessus.

Project coordination

Michel ARTHUR (CENTRE DE RECHERCHE DES CORDELIERS)

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.

Partner

INSERM-UMRS1138-CRC-Equipe 12 CENTRE DE RECHERCHE DES CORDELIERS
UPDESCARTES-LCBPT Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques
I2BC Institut de biologie intégrative de la cellule-Fonction et Architecture des Assemblages MacroMoléculaires

Help of the ANR 539,729 euros
Beginning and duration of the scientific project: - 48 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter