Daniel P Becker
Loyola University Chicago, USA
Title: Design and synthesis of DapE inhibitors as potential antibiotics with a new mechanism of action
Biography
Biography: Daniel P Becker
Abstract
There is an urgent need for antibacterial agents with new cellular mechanisms of action, and the bacterial enzyme N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) offers an excellent target for the eventual development of new antibiotics. DapE is in the succinylase pathway, which is the primary biosynthetic pathway for producing meso-diaminopimelate (m-DAP) and lysine in all Gram-negative and most Gram-positive bacteria, and is not expressed in mammals, making it a very important bacterial enzyme to study. X-ray crystallography of the DapE enzyme in the presence of our inhibitors has resulted in an atomic resolution (1.3Å) structure. Structural insights from X-ray crystallography have been coupled with molecular dynamics (MD) experiments using NAMD to explore the mechanism of the dramatic enzyme conformational changes that result in substrate binding by DapE and product release, and also using our Products-Based Transition-State Modeling (PBTSM) protocol, as we have recently described. Synthesis of analogs that we have identified from a high-throughput screen including tetrazoles and pyrazoles as well as 6- and 7-indoline sulfonamides will be described, with efforts that have been guided by docking using MOE. Synthetic efforts include methodology to access 7-substituted indolines that have previously eluded synthesis. We will also describe acyl sulfonamides prepared through Click chemistry that have the capacity to interact with both zinc atoms in dimetalloenzymes. DapE enzyme inhibitory potency has been assessed using our recently validated ninhydrin-based assay (Scheme 1) employing N-methyl-L,L-SDAP (succinyl diaminopimelate), synthesized on a large scale via an asymmetric synthesis, as will also be described.