Bacterial structures involved in modulation of antibiotic resistance
Deputy Director :
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.
Copper inhibits peptidoglycan LD-transpeptidases suppressing β-lactam resistance due to bypass of penicillin-binding proteins. Peters K, Pazos M, Edoo Z, Hugonnet JE, Martorana AM, Polissi A, VanNieuwenhze MS, Arthur M, Vollmer W. Proc Natl Acad Sci U S A. 2018; 115:10786-10791
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; 24:14911-14915.
Synthesis of Avibactam Derivatives and Activity on β-Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria. 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. Chemistry. 2018; 24:8081-8086.
Factors essential for L,D-transpeptidase-mediated peptidoglycan cross-linking and β-lactam resistance in Escherichia coli. Hugonnet JE, Mengin-Lecreulx D, Monton A, den Blaauwen T, Carbonnelle E, Veckerlé C, Brun YV, van Nieuwenhze M, Bouchier C, Tu K, Rice LB, Arthur M. Elife. 2016;5. pii: e19469.
Electrophilic RNA for Peptidyl-RNA Synthesis and Site-Specific Cross-Linking with tRNA-Binding Enzymes. Fonvielle M, Sakkas N, Iannazzo L, Le Fournis C, Patin D, Mengin-Lecreulx D, El-Sagheer A, Braud E, Cardon S, Brown T, Arthur M, Etheve-Quelquejeu M. Angew Chem Int Ed Engl. 2016; 55:13553-13557.
Routes of Synthesis of Carbapenems for Optimizing Both the Inactivation of L,D-Transpeptidase LdtMt1 of Mycobacterium tuberculosis and the Stability toward Hydrolysis by β-Lactamase BlaC.
Iannazzo L, Soroka D, Triboulet S, Fonvielle M, Compain F, Dubée V, Mainardi JL, Hugonnet JE, Braud E, Arthur M, Etheve-Quelquejeu M.
J Med Chem. 2016; 59:3427-38.