Developing Oligothioetheramides as Alternatives to Traditional Antibiotics
| dc.contributor.author | Artim, Christine Mary | |
| dc.contributor.chair | Alabi, Christopher A | |
| dc.contributor.committeeMember | Ober, Christopher K. | |
| dc.contributor.committeeMember | DeLisa, Matthew | |
| dc.contributor.committeeMember | Daniel, Susan | |
| dc.date.accessioned | 2020-08-10T20:23:38Z | |
| dc.date.available | 2021-06-08T06:00:16Z | |
| dc.date.issued | 2020-05 | |
| dc.description | 253 pages | |
| dc.description.abstract | Antibiotic resistance poses a serious threat to global health as new antibiotic development lags behind the emergence of increasingly resistant bacteria. Antimicrobial peptides offer a promising source of new antibiotics, but have not achieved broad clinical success due to factors including systemic host toxicity and susceptibility to proteolytic degradation. Oligothioetheramides (oligoTEAs) are synthetic, sequence-defined peptidomimetics designed to retain the positive traits of antimicrobial peptides with enhanced proteolytic stability. By investigating the impacts of physicochemical properties including cationic type, charge density, and backbone hydrophobicity, we demonstrate the importance of guanidinium functionalization and carefully tuned backbone hydrophobicity to achieve potent antibacterial activity with minimal mammalian cell toxicity. This knowledge was used to synthesize oligoTEAs with activities that rival clinical antibiotics. However, similar to polycationic macromolecules, oligoTEAs are toxic upon intravenous injection in vivo. We seek to mitigate this toxicity by conjugating oligoTEAs to non-toxic moieties which can shield the cationic charge. As this lowers both toxicity and activity, the conjugates contain a peptide linker which cleaves in the body to reactivate the antimicrobial agent. By controlling the linker cleavage kinetics, we seek to optimize oligoTEA reactivation for potent activity and suppression of systemic toxicity. Building upon these results, we begin investigations into antibody-oligoTEA conjugates for improved selectivity and targeting. Altogether, this body of work illustrates the potential of oligoTEAs and oligoTEA conjugates to develop therapeutics that aid in the fight against antibiotic resistance. | |
| dc.identifier.doi | https://doi.org/10.7298/zc3f-vk98 | |
| dc.identifier.other | Artim_cornellgrad_0058F_12010 | |
| dc.identifier.other | http://dissertations.umi.com/cornellgrad:12010 | |
| dc.identifier.uri | https://hdl.handle.net/1813/70358 | |
| dc.language.iso | en | |
| dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | |
| dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject | antibacterial | |
| dc.subject | antibiotic | |
| dc.subject | drug discovery | |
| dc.subject | MRSA | |
| dc.subject | oligoTEA | |
| dc.subject | polymer | |
| dc.title | Developing Oligothioetheramides as Alternatives to Traditional Antibiotics | |
| dc.type | dissertation or thesis | |
| dcterms.license | https://hdl.handle.net/1813/59810 | |
| thesis.degree.discipline | Chemical Engineering | |
| thesis.degree.grantor | Cornell University | |
| thesis.degree.level | Doctor of Philosophy | |
| thesis.degree.name | Ph. D., Chemical Engineering |
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