Bacterial structures involved in modulation of antibiotic resistance

Director : 

Michel Arthur

Deputy Director : 

Jean-Emmanuel Hugonnet

Bacterial infections remain a major cause of mortality mainly due to our inability to effectively eradicate the pathogens and to the emergence of new infectious agents. With the advances in medicine and surgery, the risk of infection has increased in recent years, particularly in situations of acquired immunodeficiency. Bacterial resistance to antibiotics is of particular concern as it now involves all classes of antibiotics and occurs in practically all pathogenic bacteria.

 

Resistance incurs additional costs linked to the use of more expensive drugs and increases in the length of hospital stays. As pathogens evolve and acquire resistance to all available antibiotics, a therapeutic deadlock will be inevitable unless new compounds are developed.
In order to combat antibiotic resistance, the structures of the “first-generation” antibiotics have been successively modified, either to restore their affinity to their targets or to render them refractory to inactivating enzymes. The use of multiple generations of antibiotics acting on the same target has led to the complex evolution of resistance mechanisms.
Our team combines expertise in biochemistry, genetics and medicinal chemistry to (i) anticipate the emergence of novel resistance mechanisms, (ii) identify new essential drug targets, and (iii) design inhibitors which specifically interact with resistance factors. We are particularly interested in the enzymes involved in the biosynthesis of the main component of the bacterial cell wall, the peptidoglycan (PG) and on antibiotics targeting this synthesis. Our current models include the mycobacteria, the enterococci, the staphylococci, and the enterobacteria. Four subjects are currently under investigation: (i) the participation of aminoacyl-tRNAs to PG synthesis; (ii) the development of new molecules targeting peptidoglycan L,D-transpeptidases and β-lactamases; (iii) the optimization of antibiotic treatments for infections due to Mycobacterium abscessus, (iv) the regulation of the peptidoglycan cross-linking pathways in enterocci and Escherichia coli.

Main publications

Genome-wide identification of genes required for alternative peptidoglycan cross-linking in Escherichia coli revealed unexpected impacts of β-lactams.

Voedts H, Kennedy SP, Sezonov G, Arthur M, Hugonnet JE. Nat Commun. 2022 Dec 27;13(1):7962. doi: 10.1038/s41467-022-35528-3.

Modulation of the Specificity of Carbapenems and Diazabicyclooctanes for Selective Activity against Mycobacterium tuberculosis.

Barnier JP, Saidjalolov S, Bouchet F, Mayer L, Edoo Z, Sayah I, Iannazzo L, Ethève-Quelquejeu M, Mainardi JL, Braud E, Arthur M.Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0235721. doi: 10.1128/aac.02357-21. Epub 2022 Aug 9.

Heavy isotope labeling and mass spectrometry reveal unexpected remodeling of bacterial cell wall expansion in response to drugs.

Atze H, Liang Y, Hugonnet JE, Gutierrez A, Rusconi F, Arthur M.Elife. 2022 Jun 9;11:e72863. doi: 10.7554/eLife.72863.

Role of endopeptidases in peptidoglycan synthesis mediated by alternative cross-linking enzymes in Escherichia coli.

Voedts H, Dorchêne D, Lodge A, Vollmer W, Arthur M, Hugonnet JE. EMBO J. 2021 Oct 1;40(19):e108126. doi: 10.15252/embj.2021108126. Epub 2021 Aug 12. PMID: 34382698

Partition of tRNAGly isoacceptors between protein and cell-wall peptidoglycan synthesis in Staphylococcus aureus.

Rietmeyer L, Fix-Boulier N, Le Fournis C, Iannazzo L, Kitoun C, Patin D, Mengin-Lecreulx D, Ethève-Quelquejeu M, Arthur M, Fonvielle M. Nucleic Acids Res. 2021 Jan 25;49(2):684-699. doi: 10.1093/nar/gkaa1242. PMID: 33367813

Click and Release Chemistry for Activity-Based Purification of β-Lactam Targets.

Saidjalolov S, Braud E, Edoo Z, Iannazzo L, Rusconi F, Riomet M, Sallustrau A, Taran F, Arthur M, Fonvielle M, Etheve-Quelquejeu M.Chemistry. 2021 May 17;27(28):7687-7695. doi: 10.1002/chem.202100653.

Impact of relebactam-mediated inhibition of Mycobacterium abscessus BlaMab β-lactamase on the in vitro and intracellular efficacy of imipenem.

Le Run E, et al. Among authors: Arthur M, Mainardi JL. J Antimicrob Chemother. 2020. PMID: 31637424

Structural insight into YcbB-mediated beta-lactam resistance in Escherichia coli.

Caveney NA, Caballero G, Voedts H, Niciforovic A, Worrall LJ, Vuckovic M, Fonvielle M, Hugonnet JE, Arthur M, Strynadka NCJ. Nat Commun. 2019 Apr 23;10(1):1849. doi: 10.1038/s41467-019-09507-0. PMID: 31015395

Synthesis of Lipid-Carbohydrate-Peptidyl-RNA Conjugates to Explore the Limits Imposed by the Substrate Specificity of Cell Wall Enzymes on the Acquisition of Drug Resistance.

Fonvielle M, Bouhss A, Hoareau C, Patin D, Mengin-Lecreulx D, Iannazzo L, Sakkas N, El Sagheer A, Brown T, Ethève-Quelquejeu M, Arthur M. Chemistry. 2018 Oct 9;24(56):14911-14915. doi: 10.1002/chem.201802360. PMID: 30020544

 

All publications