Synthesis and Biological Evaluation of New Cyclic

Il y a 2 mois

Montpellier, France IBMM, UMR 5247-CNRS-ENSCM-UM Temps plein

**Synthesis and biological evaluation of new cyclic dinucleotide analogues with antibacterial activity**:

- Réf
- **ABG-114944**
- Sujet de Thèse- 02/06/2023- Contrat doctoral- IBMM, UMR 5247-CNRS-ENSCM-UM- Lieu de travail- Montpellier - Occitanie - France- Intitulé du sujet- Synthesis and biological evaluation of new cyclic dinucleotide analogues with antibacterial activity- Champs scientifiques- Chimie
- Mots clés- organic synthesis, biochemistry, medicinal chemistry, cyclic dinucleotides**Description du sujet**:
**_This PhD is funded by the Fondation Méditéranée Infection (FMI) and the Université of Montpellier with the aim of promoting young researchers from emerging countries. _**

**_Only foreigners from emerging countries who have not been resident in France for more than one year (Master 2 accepted) are eligible to apply._**

**Background and general objectives of the project**: Cyclic dinucleotides (CDNs) are crucial cellular messenger molecules in various organisms. Purine containing CDNs such as 3’5’-c-di-GMP, c-di-AMP, 2’3’-c-GAMP and 3’3’-c-GAMP are the most studied but the recent discovery of c-di-UMP and c-UAMP in _E. coli_ suggests that CDNs containing pyrimidine nucleobase are also biosynthesized for functions that remain to be discovered.1 They regulate numerous processes in bacteria such as quorum sensing, signal transduction or control of biofilm formation.2 In particular, the c-di-GMP synthetized by the diguanylate cyclases (DGCs) was identified as playing

a central role in bacterial biofilm formation and growth. Thus, CDN analogues able to inhibit the DGCs could limit the formation of bacterial biofilm as an alternative to conventional antibiotic molecules used to treat bacterial infections in a context of rising antibiotic resistance. Therefore, we aim to synthetize and evaluate the biological activity of original CDN analogues by modifying the c-di-GMP chemical structure at the level of the internucleoside linkage, the ribose or the nucleobases. We recently developed the synthesis of original CDNs exhibiting a modified _N_-acylsulfonamide internucleoside linkage using the sulfo-click reaction.3 Following this early work, we aim to expand our library of CDN analogues and evaluate their antimicrobial activity as DGC inhibitors. This project is based on the collaboration between the ChemBioNAC team at the Institut des Biomolécules Max Mousseron in Montpellier and the laboratory Membranes et Cibles Thérapeuthiques (MCT) in Marseille.

The PhD student will have to synthesize small libraries of new CDN derivatives and screen them for their _in vitro_ activity against bacteria from the ESKAPE group by performing minimum inhibitory concentration (MIC) and biofilm inhibition assays.

**Funding**: FMI and university of Montpellier (~2000 euros gross/month)

**Location**: The chemical part of the work will be carried out in Montpellier, France and biological evaluation in Marseille, France.

**Keywords**: organic synthesis, biochemistry, medicinal chemistry, cyclic dinucleotides.

**References**:
1. Whiteley, A. T._, et al._, Bacterial cGAS-like enzymes synthesize diverse nucleotide signals. _Nature _**2019,** _567_ (7747), 194-199.

2. Yoon, S. H._, et al._, The ever-expanding world of bacterial cyclic oligonucleotide second messengers. _Curr. Opin. Microbiol. _**2021,** _60_, 96-103.

3. Amador, R._, et al._, Efficient synthesis of new Cyclic Dinucleotide analogues using the sulfo-click reaction. _submitted _**2023**.

**Prise de fonction**:

- 02/10/2023**Nature du financement**:

- Contrat doctoral**Précisions sur le financement**:

- Fondation Méditéranée Infection and university of Montpellier**Présentation établissement et labo d'accueil**:

- IBMM, UMR 5247-CNRS-ENSCM-UM**Site web**:
**Intitulé du doctorat**:

- Doctorat de chimie organique**Pays d'obtention du doctorat**:

- France**Etablissement délivrant le doctorat**:

- Université de Montpellier**Ecole doctorale**:

- ED 459 Sciences Chimiques Balard-
- 21/07/2023

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