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Dissertation
Structure-based discovery of allosteric inhibitors for H. pylori glutamate racemase
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2024
DOI: 10.25820/etd.007878
Abstract
In an era of escalating antibiotic resistance, there is a pressing need for innovative strategies to develop novel antibiotics. Gram-negative bacteria, characterized by their robust dual-membrane, are intrinsically resistant to a wide range of antibiotics and can readily develop new resistances. Members of this bacterial class comprise several pathogenic organisms, including the primary cause of gastric cancer, Helicobacter pylori (H. pylori). Glutamate racemase (MurI) is an indispensable bacterial enzyme, responsible for the conversion of L-glutamate to D-glutamate. D-glutamate is integrated in the pentapeptide sidechain that bridges adjacent glycan polymers, reinforcing the peptidoglycan layer and safeguarding bacterial cells against osmotic rupture. By exploiting allosteric regulation of H. pylori MurI, a new series of antibiotics were identified. These compounds displayed a diverse range of activity in preventing H. pylori proliferation, with the most potent hit capable of full growth inhibition for metronidazole and clarithromycin resistant H. pylori strains. Alongside the introduction of a novel antibiotic for this carcinogenic pathogen, the innovative use of readily accessible chemical space holds great promise for Gram-negative antibiotic development as a whole.
Details
- Title: Subtitle
- Structure-based discovery of allosteric inhibitors for H. pylori glutamate racemase
- Creators
- Jonah Propp
- Contributors
- Michael Ashley Spies (Advisor)Jonathan Doorn (Committee Member)David Roman (Committee Member)Nicholas Schnicker (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy (Medicinal and Natural Products Chemistry)
- Date degree season
- Spring 2024
- DOI
- 10.25820/etd.007878
- Publisher
- University of Iowa
- Number of pages
- xiii, 92 pages
- Copyright
- Copyright 2024 Jonah Propp
- Grant note
- The Advanced Photon Source is a U.S. Department of Energy (DOE) Office of Science user facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Beamline 4.2.2 of the Advanced Light Source, a U.S. DOE Office of Science User Facility under Contract No. DE-AC02-05CH11231, is supported in part by the ALS-ENABLE program funded by the National Institutes of Health (NIH), National Institute of General Medical Sciences, grant P30 GM124169-01. This work was supported by NIH grants awarded to M. A. Spies (R01-GM09737 and R01-GM138471).
- Language
- English
- Date submitted
- 04/17/2024
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 79-84).
- Public Abstract (ETD)
- Helicobacter pylori (H. pylori) is a bacterium responsible for several forms of gastric disease, including gastric cancer. H. pylori is part of the Gram-negative bacterial family, which all share a cell wall with an outer membrane. This extra barrier makes it difficult for drugs to pass into the cell, making bacteria like H. pylori resistant to a wide range of antibiotics. One of the enzymes responsible for building the cell wall, glutamate racemase, has been confirmed as a drug target to treat H. pylori infections. In my research, I have worked to characterize potential H. pylori antibiotics and discover new ones by targeting glutamate racemase. To accomplish this, I used computational drug discovery, which allowed me to look at which compounds out of millions might work as a drug. I tested the most promising compounds to see how they interacted with glutamate racemase, and eventually H. pylori cells. Through this approach, I was able to identify a new series of antibiotics for H. pylori, offering new hope in combating gastric diseases.
- Academic Unit
- Pharmacy
- Record Identifier
- 9984830730002771
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