Journal of Drug Metabolism & Toxicology
Open Access

Mycobacterium tuberculosis cell-wall biosynthesis as target of carbapenems

World Congress and Exhibition on Antibiotics

September 14-16, 2015 Las Vegas, USA

Mario A Bianchet, Sabri E Bora, Radhika Gupta, Leighanne Basta, Anita Gosh, Ying Pan and William Bishai

Johns Hopkins University School of Medicine, USA

Scientific Tracks Abstracts: J Drug Metab Toxicol

Abstract :

Transpeptidases play essential roles in the bacterial cell-wall biosynthesis. Inter-stems cross-links made for these enzymes assemble the peptidoglycan mesh that confer mechanic stability to the bacteria. �?²-lactam antibiotics, penincillin, inactivates (4-3) DD-transpeptidases. These transpeptidases also called penincillin-binding proteins, cross-linked-centers of the fourth residue main-chain with that of the third residue side-chain of adjacent peptidoglycan stems. Most bacteria utilize(4-3) crosslinks to build their peptidoglycan layer. However, the Mycobacterium genus and some penicillin-resistant bacteriaâ�?�?involved in nosocomial infectionsâ�?�?majoritarily utilize the (3,3)-crosslinks carried out by (3,3) LD-transpeptidases. This (3,3)-crosslink joins the L-center of the third residue main-chain and the D-center of the another third residue mainchain of an adjacent stem. The use of this crosslink and the presence of a potent �?²-lactamase (BlaC) confers to mycobacteria resistance to penicillin and other antibiotics that mimic the D-Ala4-D-Alanyl5 terminal region of the pentapeptide donor stem recognized by DD-transpeptidases. LD-transpeptidases are resilient to this type of inhibition because they exclusively recognize a tetrapeptidedonor stem lacking the D-alanyl terminal. Carbapenems are �?²-lactam antibiotics that have a carbon atom replacing the sulphur atom at position1 of the penicillin core. This class of antibiotics inactivate LD-transpeptidases by a quasi-irreversible acylation of the enzyme catalytic cysteine, resulting in a effective agent to treat these penicillin-resistant bacteria. We are going to discuss our recent structural, biophysical, and biochemical characterization of members of this family of enzymes and their complexes with a series of carbapenemsin medical use.

Biography :

Mario A Bianchet has completed his PhD from The University of La Plata, Argentine, and performed Postdoctoral studies at Johns Hopkins University School of Medicine, where he is now a Assistant Professor of Neurology since 2011. He has published 65 papers in reputed journals. As structural enzymologist and expert in ligand recognition, he has participated in several seminal structural and mechanistic studies of macromolecules and ligand/macromolecule interactions of biomedical interest. He has important contributions to different fields, including bioenergetics: F1-ATPase, xenobiotic-response: NADPH:Quinone oxidoreductases, DNA-repair: Uracyl-Glycosylase/inhibitors, carbohydrate-recognition: animal lectins, and late stage cell-wall biosynthesis: LD-transpeptidases and their complexes with substrates and carbapenems.

Email: bianchet@jhmi.edu