Combatting bacterial pathogens : design, evaluation, and introduction of novel guanidinium-rich antiobiotic conjugates
Abstract/Contents
- Abstract
- The global challenge of antibiotic resistance necessitates the introduction of more effective antibiotics. Antibiotic resistance can result in life-threating infections, where bacteria are able to survive even in the presence of high concentrations of antibiotics due to mechanisms such as drug efflux, target modification, and enzymatic deactivation of antimicrobials. Another challenge associated with difficult-to-treat bacterial infections is the formation of biofilms, or communities of bacterial cells enmeshed in a self-produced extracellular matrix. Biofilms can form on indwelling medical devices such as catheters and prosthetic joints and are often associated with chronic and recurrent infections. Many antibiotics target processes associated with active bacterial cell growth and division but are ineffective against the metabolically dormant or slow-growing cells found in bacterial biofilms. Antibiotics may also exhibit poor or incomplete penetration through the biofilm extracellular matrix. There is an urgent need for more antibiotics to treat urgent-threat pathogens, antibiotic-resistant strains, and bacterial biofilms. This dissertation describes the design, evaluation, and introduction of new antibiotic conjugates to combat bacterial pathogens. We report a potentially general design strategy, exemplified with vancomycin, that improves and expands antibiotic performance. Vancomycin is one of the most important antibiotics in use today for the treatment of Gram-positive infections. However, it fails to eradicate difficult-to-treat biofilm populations. Vancomycin is also ineffective in killing Gram-negative bacteria due to its inability to breach the outer membrane. Having shown previously that the spatial array (linear versus dendrimeric) of multiple guanidinium groups affects cell permeation, we report here for the first time vancomycin conjugates with dendrimerically displayed guanidinium groups that exhibit superior efficacy and breadth, with lead compound V-triguan-6C representing a broad-spectrum compound with excellent activity against VRE, Gram-negative ESKAPE pathogens, and S. aureus biofilms. Mode-of-action studies reveal cell-surface activity and enhanced vancomycin-like killing. The V-triguan conjugates exhibit no acute mammalian cell toxicity or hemolytic activity. We also investigated other cationic surrogates for the guanidinium group and evaluated the first vancomycin-biguanide antibiotic conjugates. One of these compounds—V-C6-Bg-ChloA—has the best broad-spectrum activity to-date, with efficacy against VRE, and Gram-negative pathogens as well as both Gram-positive and Gram-negative biofilms. Finally, we discuss the unique activity of vancomycin-octa-arginine (V-r8) against V. cholerae. V-r8 exhibits rapid killing against V. cholerae and results in the formation of intracellular inclusion bodies. Our studies introduce new classes of broad-spectrum vancomycin derivatives and highlight the potential to improve or expand antibiotic performance through combined mode-of-action and function-oriented design studies.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Chosy, Madeline Bryant |
|---|---|
| Degree supervisor | Cegelski, Lynette |
| Thesis advisor | Cegelski, Lynette |
| Thesis advisor | Dassama, Laura |
| Thesis advisor | Wender, Paul A |
| Degree committee member | Dassama, Laura |
| Degree committee member | Wender, Paul A |
| Associated with | Stanford University, School of Humanities and Sciences |
| Associated with | Stanford University, Department of Chemistry |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Madeline Chosy. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/pn681dj3883 |
Access conditions
- Copyright
- © 2023 by Madeline Bryant Chosy
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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