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Bacterial structures involved in the modulation of antibiotic resistance

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 objective is to gain a better understanding of this evolution 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.

Our current models include the mycobacteria, the enterococci, and the enterobacteria. We have shown that the peptidoglycan of Mycobacterium tuberculosis is polymerized by a new class of enzymes, L,D-transpeptidases, that by-pass the classical penicillin-binding proteins. These enzymes are irreversibly inactivated by a particular class of β-lactams, the carbapenems, which are currently evaluated for the treatment of extensively-drug resistant tuberculosis. In parallel, the basis of the specificity of L,D-transpeptidases for carbapenems is investigated to obtain M. tuberculosis-specific drugs. A second objective concerns the characterization of new targets that have the particularity to use aminoacyl-tRNAs as substrate (Fem transferases). We have developed an original route of synthesis of peptidyl-RNA conjugates that have recently yielded picomolar inhibitors and resolution of the X-ray structure of a Fem-RNA
nucleoprotein complex.  

 Team Leader : Michel ARTHUR (Dr)

Team Members :  Fabrice COMPAIN (Dr), Matthieu FONVIELLE (Dr),  Jean-Emmanuel HUGONNET (Dr), Marie LAVOLLAY (Dr), David LEBEAUX (Dr), Jean-Luc MAINARDI (Pr).

Antoine BOUGOÜIN (Eng), Celine BUON (Eng), Delphine DORCHENE (Tec), Nicolas FIX BOULIER (Eng), Grazyna RACZKA (Tec).

Zainab EDOO (PhD), Eva LE RUN (PhD), Nicolas SAKKAS (PhD)

Administration :

Contact details: 33 1 44 27 54 55

Selected Publications

  • Triboulet S, Bougault CM, Laguri C, Hugonnet JE, Arthur M, Simorre JP. Acyl acceptor recognition by Enterococcus faecium l,d-transpeptidase Ldtfm. Mol Microbiol. 2015
  • Soroka D, Dubée V, Soulier-Escrihuela O, Cuinet G, Hugonnet JE, Gutmann L, Mainardi JL, Arthur M. Characterization of broad-spectrum Mycobacterium abscessus class A β-lactamase. J Antimicrob Chemother. 2014. 69:691-6.
  • Triboulet S, Arthur M, Mainardi JL, Veckerlé C, Dubée V, Nguekam-Moumi A, Gutmann L, Rice LB, Hugonnet JE. Inactivation kinetics of a new target of beta-lactam antibiotics. J Biol Chem. 2011. 286:22777-84.
  • Fonvielle M, Li de La Sierra-Gallay I, El-Sagheer AH, Lecerf M, Patin D, Mellal D, Mayer C, Blanot D, Gale N, Brown T, van Tilbeurgh H, Ethève-Quelquejeu M, Arthur M. The structure of FemXWv in complex with a peptidyl-RNA conjugate: mechanism of aminoacyl transfer from Ala-tRNAAla to peptidoglycan precursors. Angew Chem Int Ed Engl. 2013. 52:7278-81.
  • Lecoq L, Bougault C, Hugonnet JE, Veckerlé C, Pessey O, Arthur M, Simorre JP. Dynamics induced by β-lactam antibiotics in the active site of Bacillus subtilis L,D-transpeptidase. Structure. 2012. 20:850-61.
  • Gupta R, Lavollay M, Mainardi JL, Arthur M, Bishai WR, Lamichhane G. The Mycobacterium tuberculosis protein LdtMt2 is a non-classical transpeptidase required for virulence and resistance to amoxicillin. Nat Med. 2010. 16:466-9.

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