Mario A Bianchet
Johns Hopkins University School of Medicine, USA
Title: Mycobacterium tubercolosis cell-wall biosynthesis as target of Carbapenems
Biography
Biography: Mario A Bianchet
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. β-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 bacteria—involved in nosocomial infections—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 main-chain of an adjacent stem. The use of this crosslink and the presence of a potent β-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 β-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.
