The rapid emergence and spread of antibiotic resistant bacteria underscores the need for research and discovery of antibiotics with a new mechanism of action. A promising antimicrobial target in all Gram-negative and most Gram-positive bacteria is the DapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase enzyme. DapE is a crucial enzyme in the lysine biosynthetic pathway of bacteria for production of lysine and meso-diaminopimelate (m-DAP), which are essential for bacterial protein and peptidoglycan cell wall synthesis. DapE is not expressed in mammals; therefore, DapE inhibitors should display selective toxicity against bacteria and be free from mechanism-based side effects in humans. We have reported an atomic resolution (1.3 Å) X-ray crystal structure (PDB 5UEJ) revealing the presence of two negatively charged sulfate ions in the active site that were confirmed to bind to the same positions of the terminal carboxylates of the substrate. We therefore have modeled and synthesized bis-sulfonates with 4 to 12 methylene groups in the connecting chain to study the key Coulombic interactions in the conformational change of the enzyme from the open to closed conformer, which will lead to more potent inhibitors and eventually a novel antibiotic. Molecular dynamics simulations of the bis-sulfonates of varying chain lengths were prepared using VMD and performed using NAMD. The inhibitory potency of sulfate and other lead molecules synthesized by our research group were determined using our ninhydrin-based assay. Further characterization of the structure-activity relationship (SAR) was obtained using a thermal shift assay (TSA) to determine stabilization of the enzyme-inhibitor complex. Results of the molecular dynamics simulations and IC50 and Tm data will be discussed.

Molecular dynamics and synthesis of DapE bacterial enzyme inhibitors as potential novel antibiotics

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