Protein Synthesis and Bioconjugation for Design of Antimicrobial Conjugates
New antimicrobial approaches are needed to combat the threat of antibiotic resistance. Gram- negative bacteria are of significant clinical concern, in part due to their cell wall structure that restricts the transport of most antibiotics. Here we describe the development of two chemical strategies t...
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| Format: | Thesis |
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Massachusetts Institute of Technology
2023
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| Online Access: | https://hdl.handle.net/1721.1/147363 https://orcid.org/0000-0001-6782-0992 |
| _version_ | 1826206407255392256 |
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| author | Saebi, Azin |
| author2 | Pentelute, Bradley L. |
| author_facet | Pentelute, Bradley L. Saebi, Azin |
| author_sort | Saebi, Azin |
| collection | MIT |
| description | New antimicrobial approaches are needed to combat the threat of antibiotic resistance. Gram- negative bacteria are of significant clinical concern, in part due to their cell wall structure that restricts the transport of most antibiotics. Here we describe the development of two chemical strategies that are positioned well to expand non-traditional antibiotic approaches to breach the gram-negative cell wall, particularly in Pseudomonas aeruginosa. The first strategy, chemical synthesis of proteins, enables access to proteins equipped with modifications and conjugation handles that are valuable for unlocking their therapeutic potential. We used this approach to produce a synthetic antipseudomonal bacteriocin and demonstrated that its physical and biological characteristics were comparable to its biological counterpart. The second strategy, protein-protein conjugation, is a powerful approach for the development of targeted antibiotics. We developed a protein-protein conjugation method based on Pd-mediated cross-coupling chemistry to perform conjugation reactions under mild and dilute conditions that are amenable to most proteins. Together, these strategies have the potential to generate new and non-traditional antibiotics. |
| first_indexed | 2024-09-23T13:29:20Z |
| format | Thesis |
| id | mit-1721.1/147363 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:29:20Z |
| publishDate | 2023 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1473632023-01-20T03:27:58Z Protein Synthesis and Bioconjugation for Design of Antimicrobial Conjugates Saebi, Azin Pentelute, Bradley L. Buchwald, Stephen L. Massachusetts Institute of Technology. Department of Chemistry New antimicrobial approaches are needed to combat the threat of antibiotic resistance. Gram- negative bacteria are of significant clinical concern, in part due to their cell wall structure that restricts the transport of most antibiotics. Here we describe the development of two chemical strategies that are positioned well to expand non-traditional antibiotic approaches to breach the gram-negative cell wall, particularly in Pseudomonas aeruginosa. The first strategy, chemical synthesis of proteins, enables access to proteins equipped with modifications and conjugation handles that are valuable for unlocking their therapeutic potential. We used this approach to produce a synthetic antipseudomonal bacteriocin and demonstrated that its physical and biological characteristics were comparable to its biological counterpart. The second strategy, protein-protein conjugation, is a powerful approach for the development of targeted antibiotics. We developed a protein-protein conjugation method based on Pd-mediated cross-coupling chemistry to perform conjugation reactions under mild and dilute conditions that are amenable to most proteins. Together, these strategies have the potential to generate new and non-traditional antibiotics. Ph.D. 2023-01-19T18:48:17Z 2023-01-19T18:48:17Z 2022-09 2022-10-25T17:28:02.970Z Thesis https://hdl.handle.net/1721.1/147363 https://orcid.org/0000-0001-6782-0992 In Copyright - Educational Use Permitted Copyright MIT http://rightsstatements.org/page/InC-EDU/1.0/ application/pdf Massachusetts Institute of Technology |
| spellingShingle | Saebi, Azin Protein Synthesis and Bioconjugation for Design of Antimicrobial Conjugates |
| title | Protein Synthesis and Bioconjugation for Design of Antimicrobial Conjugates |
| title_full | Protein Synthesis and Bioconjugation for Design of Antimicrobial Conjugates |
| title_fullStr | Protein Synthesis and Bioconjugation for Design of Antimicrobial Conjugates |
| title_full_unstemmed | Protein Synthesis and Bioconjugation for Design of Antimicrobial Conjugates |
| title_short | Protein Synthesis and Bioconjugation for Design of Antimicrobial Conjugates |
| title_sort | protein synthesis and bioconjugation for design of antimicrobial conjugates |
| url | https://hdl.handle.net/1721.1/147363 https://orcid.org/0000-0001-6782-0992 |
| work_keys_str_mv | AT saebiazin proteinsynthesisandbioconjugationfordesignofantimicrobialconjugates |