Structure-activity relationships of niclosamide to overcome colistin resistance
| dc.contributor.author | Berry, Liam | |
| dc.contributor.examiningcommittee | Davis, Rebecca (Chemistry) | |
| dc.contributor.examiningcommittee | Kumar, Ayush (Microbiology) | |
| dc.contributor.examiningcommittee | Zhanel, George (MMID) | |
| dc.contributor.examiningcommittee | Boddy, Christopher (University of Ottawa) | |
| dc.contributor.supervisor | Schweizer, Frank | |
| dc.date.accessioned | 2024-08-30T14:10:38Z | |
| dc.date.available | 2024-08-30T14:10:38Z | |
| dc.date.issued | 2024-08-27 | |
| dc.date.submitted | 2024-08-28T00:11:29Z | en_US |
| dc.date.submitted | 2024-08-29T22:42:40Z | en_US |
| dc.degree.discipline | Chemistry | |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | |
| dc.description.abstract | Antibacterial resistance poses a significant threat to global healthcare systems, particularly against Gram-negative bacteria (GNB). Addressing this challenge requires urgent development of new therapies, especially given the emergence of resistance even to last-resort antibiotics like colistin. However, rising rates of colistin resistance highlight the need for alternative strategies. One promising approach involves repurposing existing drugs, such as the anthelmintic niclosamide, known to enhance colistin activity in combination therapy. Despite its potential, niclosamide faces limitations due to poor solubility, bioavailability, and off-target toxicity. Thus, repurposing it as an antibacterial agent necessitates the synthesis of new derivatives capable of overcoming these challenges. Additionally, a comprehensive exploration of niclosamide's structure–activity relationship (SAR) against GNB remains unexplored. We synthesized a series of niclosamide analogs to address these gaps, focusing on three main objectives: mitigating toxicity by replacing the nitro group, modifying the central amide moiety, and designing niclosamide-based hybrid antibiotics. Our SAR investigation led to the discovery of several lead compounds with comparable colistin-potentiating activity to niclosamide but with reduced cytotoxicity. Notably, we also identified synergy with antibiotics beyond colistin, including cefiderocol and bacitracin. Overall, our work provides critical insights into synthetic strategies for developing new niclosamide derivatives. We also demonstrate that toxicity to mammalian cells can be minimized while maintaining colistin potentiation and reveal promising avenues for repurposing niclosamide in combating antibacterial resistance. | |
| dc.description.note | October 2024 | |
| dc.identifier.uri | http://hdl.handle.net/1993/38464 | |
| dc.language.iso | eng | |
| dc.rights | open access | en_US |
| dc.subject | Medicinal Chemistry | |
| dc.title | Structure-activity relationships of niclosamide to overcome colistin resistance | |
| dc.type | doctoral thesis | en_US |
| local.subject.manitoba | no |