Approaches to investigating antibiotic efficacy and discovery of treatment strategies against antibiotic tolerance
While it is widely understood that antibiotic resistance is challenging the efficacy of our antibiotic therapies, there is a growing appreciation for the clinical importance of other ways that bacteria can survive antibiotic treatment. In particular, antibiotic tolerance describes a set of phenotype...
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| Format: | Thesis |
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Massachusetts Institute of Technology
2024
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| Online Access: | https://hdl.handle.net/1721.1/153464 |
| _version_ | 1826217348403560448 |
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| author | Andrews, Ian Wayne |
| author2 | Collins, James J. |
| author_facet | Collins, James J. Andrews, Ian Wayne |
| author_sort | Andrews, Ian Wayne |
| collection | MIT |
| description | While it is widely understood that antibiotic resistance is challenging the efficacy of our antibiotic therapies, there is a growing appreciation for the clinical importance of other ways that bacteria can survive antibiotic treatment. In particular, antibiotic tolerance describes a set of phenotypes where genetically susceptible bacteria can survive antibiotic treatment. Thus, there is a need for methods to improve our understanding of currently used antibiotics, as well as the discovery and development of new antibiotic therapeutic strategies, particularly focused on addressing antibiotic tolerance.
In this thesis, I present advancements to our understanding of antibiotic efficacy and our methods for discovering treatment strategies against antibiotic tolerant bacterial populations. First, I present an investigation into the metabolic processes that drive beta-lactam lethality, where we showed that drug-induced disruption of anabolic- catabolic homeostasis is an important factor for beta-lactam activity. Next, I describe an approach towards the discovery of antibiotic adjuvants for treating antibiotic tolerance. Finally, I present work towards the development of a method for discovering new antibiotics with activity against antibiotic tolerant bacteria. I describe characterization of compounds that were identified in primary screening efforts, as well as the results of a deep learning approach to this challenge in antibiotic discovery. Together, these projects demonstrate a set of advancements in our understanding of antibiotic activity and towards the challenge of antibiotic discovery. |
| first_indexed | 2024-09-23T17:02:13Z |
| format | Thesis |
| id | mit-1721.1/153464 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T17:02:13Z |
| publishDate | 2024 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1534642024-02-09T03:01:12Z Approaches to investigating antibiotic efficacy and discovery of treatment strategies against antibiotic tolerance Andrews, Ian Wayne Collins, James J. Massachusetts Institute of Technology. Department of Biological Engineering While it is widely understood that antibiotic resistance is challenging the efficacy of our antibiotic therapies, there is a growing appreciation for the clinical importance of other ways that bacteria can survive antibiotic treatment. In particular, antibiotic tolerance describes a set of phenotypes where genetically susceptible bacteria can survive antibiotic treatment. Thus, there is a need for methods to improve our understanding of currently used antibiotics, as well as the discovery and development of new antibiotic therapeutic strategies, particularly focused on addressing antibiotic tolerance. In this thesis, I present advancements to our understanding of antibiotic efficacy and our methods for discovering treatment strategies against antibiotic tolerant bacterial populations. First, I present an investigation into the metabolic processes that drive beta-lactam lethality, where we showed that drug-induced disruption of anabolic- catabolic homeostasis is an important factor for beta-lactam activity. Next, I describe an approach towards the discovery of antibiotic adjuvants for treating antibiotic tolerance. Finally, I present work towards the development of a method for discovering new antibiotics with activity against antibiotic tolerant bacteria. I describe characterization of compounds that were identified in primary screening efforts, as well as the results of a deep learning approach to this challenge in antibiotic discovery. Together, these projects demonstrate a set of advancements in our understanding of antibiotic activity and towards the challenge of antibiotic discovery. Ph.D. 2024-02-08T15:11:14Z 2024-02-08T15:11:14Z 2022-05 2024-02-02T20:55:40.718Z Thesis https://hdl.handle.net/1721.1/153464 In Copyright - Educational Use Permitted Copyright MIT http://rightsstatements.org/page/InC-EDU/1.0/ application/pdf Massachusetts Institute of Technology |
| spellingShingle | Andrews, Ian Wayne Approaches to investigating antibiotic efficacy and discovery of treatment strategies against antibiotic tolerance |
| title | Approaches to investigating antibiotic efficacy and discovery of treatment strategies against antibiotic tolerance |
| title_full | Approaches to investigating antibiotic efficacy and discovery of treatment strategies against antibiotic tolerance |
| title_fullStr | Approaches to investigating antibiotic efficacy and discovery of treatment strategies against antibiotic tolerance |
| title_full_unstemmed | Approaches to investigating antibiotic efficacy and discovery of treatment strategies against antibiotic tolerance |
| title_short | Approaches to investigating antibiotic efficacy and discovery of treatment strategies against antibiotic tolerance |
| title_sort | approaches to investigating antibiotic efficacy and discovery of treatment strategies against antibiotic tolerance |
| url | https://hdl.handle.net/1721.1/153464 |
| work_keys_str_mv | AT andrewsianwayne approachestoinvestigatingantibioticefficacyanddiscoveryoftreatmentstrategiesagainstantibiotictolerance |