Major
Chemistry
Anticipated Graduation Year
2022
Access Type
Open Access
Abstract
An ongoing effort continues against the rising tide of antibiotic resistant bacteria, underscoring the urgent need to discover antibiotics with a novel mechanism of action. To this end, we have focused on the inhibition of the bacterial enzyme N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE). Guided by docking with the computational suite Molecular Operating Environment (MOE) and lead molecules obtained through a HiTS (High Throughput Screening) assay, several lead molecules and analogs were identified, synthesized, and optimized by our research group. These potential new inhibitors are tested in our recently described and updated biochemical DapE ninhydrin assay, with IC50 data obtained for inhibitors including cyclobutanone, tetrazole, pyrazole, sultam, and indoline sulfonamide analogs. To gain a greater understanding of the thermodynamic effects of these inhibitors on the binding of these synthesized analogs with the DapE enzyme, we have employed a Thermal Shift Assay (TSA).
Community Partners
Northwestern Center for Structural Genomics of Infectious Diseases
Faculty Mentors & Instructors
Dr. Daniel Becker, Professor, Department of Chemistry; Emma Kelley, Graduate Student, Department of Chemistry
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Evaluation of DapE Inhibitors Utilizing the DapE Ninhydrin and Thermal Shift Assays Toward the Discovery of Novel Antibiotics
An ongoing effort continues against the rising tide of antibiotic resistant bacteria, underscoring the urgent need to discover antibiotics with a novel mechanism of action. To this end, we have focused on the inhibition of the bacterial enzyme N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE). Guided by docking with the computational suite Molecular Operating Environment (MOE) and lead molecules obtained through a HiTS (High Throughput Screening) assay, several lead molecules and analogs were identified, synthesized, and optimized by our research group. These potential new inhibitors are tested in our recently described and updated biochemical DapE ninhydrin assay, with IC50 data obtained for inhibitors including cyclobutanone, tetrazole, pyrazole, sultam, and indoline sulfonamide analogs. To gain a greater understanding of the thermodynamic effects of these inhibitors on the binding of these synthesized analogs with the DapE enzyme, we have employed a Thermal Shift Assay (TSA).