Antibiotics and Antibiotic Resistance

Biography

Biography: Mario A Bianchet

Abstract

Multidrug-resistant microorganisms produce infections that are hard to treat or may even be untreatable with conventional antimicrobials. Mycobacteria tuberculosis (Mtb), Clostridae difficile (Cd), and ESKAPE pathogens are capable of developing resistance to not only clinical antibiotics, but to the last resort (such as carbapenems) as well. The development of novel treatment options to replace antibiotics that lost their effectiveness and new antibiotic targets to circumvent target-specific resistance, which has emerged against every antibiotic class, are high priorities.The development of the necessary new antibiotics through trial-and-error is a costly and time-consuming proposition. Structure-based drug design accelerates discovery by linking structural information and computational techniques. The targeting late stages of bacterial cell-wall biosynthesis remains a sound strategy. The peptidoglycan of Mtb, M. abscessus, and Cd during stationary growth is synthetized by LD-transpeptidases (LDTs), different enzyme than DD-transpeptidases (Penicillin-binding proteins) the primary target of β-lactams. This difference contributes to these pathogens resistance to β-lactams. We are investigating the molecular structures of Mtb LDTs and its complexes with carbapenems. Structural evidence from these studies suggests that the catalytic site flexibility dynamically accommodates ligands larger that than the geometric volume of the site observed in the crystallographic structure. Thus, inhibitors binding to LDTs can involve transient active-site conformations unobserved in the time-averaged crystallographic structure. We are developing methods to seek LDTs inhibitors targeting accessible dynamic states of these enzymes in drug-resistant pathogens to obtain antibiotic leads. In this talk, I’ll present preliminary results of our work targeting essential Mtb transpeptidase, LdtMt2