New insights into the inhibition of known targets

Retour aux sujets Retour à BactResist

New insights into the inhibition of known targets

Mechanisms of β-lactam and glycopeptide resistance, and target inhibition. The evolution of low-affinity penicillin-binding proteins (PBPs) underlies β-lactam resistance in Gram-positive bacteria. However, the catalytic mechanism of peptidoglycan cross-linking remains poorly characterized due to the lack of defined substrates. Using enterococci as a model, we investigate how PBPs recognize peptidoglycan precursors using synthetic substrate surrogates. Our goal is to define the structural and functional constraints governing resistance acquisition and to design robust assays for the identification of novel transpeptidase inhibitors.

Expanding the therapeutic potential of DBOs. Diazabicyclooctanes (DBOs), such as avibactam and relebactam, were initially developed as β-lactamase inhibitors against Gram-negative pathogens. We recently demonstrated that DBOs also inhibit L,D-transpeptidases, key enzymes in mycobacterial cell wall polymerization. We aim to optimize the DBO scaffold for activity against Mycobacterium tuberculosis in collaboration with our chemistry partner, leveraging original synthetic routes that have led to two patents.

Associated publications:

  • Cusumano JA, Daffinee KE, Ugalde-Silva P, Peti W, Arthur M, Desbonnet C, Rice LB, LaPlante KL, García-Solache M. Penicillin-Binding Proteins and Alternative Dual-Beta-Lactam Combinations for Serious Enterococcus faecalis Infections with Elevated Penicillin MICs. Antimicrob Agents Chemother. 2023 Feb 16;67(2):e0087122.

  • Hunashal Y, Kumar GS, Choy MS, D’Andréa ÉD, Da Silva Santiago A, Schoenle MV, Desbonnet C, Arthur M, Rice LB, Page R, Peti W. Molecular basis of β-lactam antibiotic resistance of ESKAPE bacterium E. faecium Penicillin Binding Protein PBP5. Nat Commun. 2023. 17;14(1):4268. doi: 10.1038/s41467-023-39966-5.

  • Hunashal Y, Fonvielle M, Kobayashi MT, Choy MS, Kumar GS, Silva PU, Liang Y, Desbonnet C, Rice LB, Arthur M, Page R, Peti W. Peptidoglycan recruitment by a penicillin binding protein. Nat Commun. 2025; 16(1):11244. doi: 10.1038/s41467-025-66095-y.

  • Edoo Z, Iannazzo L, Compain F, Li de la Sierra Gallay I, van Tilbeurgh H, Fonvielle M, Bouchet F, Le Run E, Mainardi JL, Arthur M, Ethève-Quelquejeu M, Hugonnet JE. Peptidoglycan Biosynthesis Enzymes of Mycobacteria. Chemistry. 2018; 24(32):8081-8086. doi: 10.1002/chem.201800923.