{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/115675"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/115675","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Amphotericin B extracts ergosterol faster than fungi can make it","abstract":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01","abstract_html":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01","abstract_has_math":false,"creators":["Zhang, Jiabao"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["Burke, Martin D","Chan, Jefferson","Mitchell, Douglas A","Rienstra, Chad M"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-05","date_published":"2022-05","updated_at":"2026-07-22T22:24:54Z","subjects":["AmB","ergosterol","sterol sponge"],"languages":["en","eng"],"rights":["Jiabao Zhang owns the copyright of this dissertation."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/115675","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Burke, Martin D","Chan, Jefferson","Mitchell, Douglas A","Rienstra, Chad M"]},{"key":"dc:creator","label":"Author","values":["Zhang, Jiabao"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2022-05","2022-04-04"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["AmB","ergosterol","sterol sponge"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Jiabao Zhang owns the copyright of this dissertation."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/115675"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01","The student, Jiabao Zhang, accepted the attached license on 2022-03-28 at 16:59.","The student, Jiabao Zhang, submitted this Dissertation for approval on 2022-03-28 at 17:13.","This Dissertation was approved for publication on 2022-04-04 at 16:37.","DSpace SAF Submission Ingestion Package generated from Vireo submission #17552 on 2022-11-11 at 12:18:47","Invasive fungal infections significantly affect immunocompromised patients’ health,causing millions of deaths each year. Amphotericin B (AmB) has been used as a last-line fungicidal antimicrobial for over 60 years with severe toxicity and disputed mechanisms of action. We discovered that AmB primarily kills fungi by the formation of large extramembranous aggregates, which rapidly bind to extract sterols from lipid bilayers, guiding the future development of AmB derivatives. A predicted sterol-selective derivative C2’epiAmB was synthesized with two different routes. This compound was confirmed to only bind ergosterol but not cholesterol. As a result, C2’epiAmB showed good potency to fungal cells but not human cells.Comprehensive experiments were completed to validate its safety profile and it showed superior efficacy in a mice disease model. Meanwhile, C2’epiAmB displayed reduced potency in several strains when compared with AmB. We systematically examined this difference and found that the ergosterol extraction rate primarily determines the potency, further elucidating our sterol sponge mechanism. With the sterol sponge mechanism established in AmB, the investigation of other glycosylated polyene macrolides’(GPM) mode of action was also performed. A highly conserved substructure among this class of natural products was utilized to expand GPM biosynthetic gene clusters (BGC). Kineosporicin, a first reported methyltetraene natural product, was discovered enabled by BGC analysis. This newly discovered GPM and other representative GPMs from different classes were further tested and confirmed that the sterol sponge mechanism was conserved in the GPM family. In addition, the ergosterol extraction mechanism was validated in leishmaniasis by using two AmB urea derivatives, AmB methyl urea (AmB-MU) and ethyl amino urea (AmB-AU). AmB-MU was also found well-tolerated and more effective when compared to AmB in a mice model. These studies demonstrated that besides looking at different formulations of AmB, derivatizing AmB could be an important way to improve its therapeutics in this prevalent disease. Lastly, we discovered a renal-sparing, fungicidal AmB derivative with combining the toxicity-eliminating C2’ modification and potency-increasing modification at C41 enabled by accelerating the ergosterol extraction rate. For the first time, this new derivative AM-2-19 achieved eradication of fungal infections in mice without causing toxicity. It is an up-and-coming drug candidate to help millions of patients."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Amphotericin B extracts ergosterol faster than fungi can make it"]}]}],"canonical_facts":{"dc:contributor":["Burke, Martin D","Chan, Jefferson","Mitchell, Douglas A","Rienstra, Chad M"],"dc:creator":["Zhang, Jiabao"],"dc:date":["2022-05","2022-04-04"],"dc:description":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01","The student, Jiabao Zhang, accepted the attached license on 2022-03-28 at 16:59.","The student, Jiabao Zhang, submitted this Dissertation for approval on 2022-03-28 at 17:13.","This Dissertation was approved for publication on 2022-04-04 at 16:37.","DSpace SAF Submission Ingestion Package generated from Vireo submission #17552 on 2022-11-11 at 12:18:47","Invasive fungal infections significantly affect immunocompromised patients’ health,causing millions of deaths each year. Amphotericin B (AmB) has been used as a last-line fungicidal antimicrobial for over 60 years with severe toxicity and disputed mechanisms of action. We discovered that AmB primarily kills fungi by the formation of large extramembranous aggregates, which rapidly bind to extract sterols from lipid bilayers, guiding the future development of AmB derivatives. A predicted sterol-selective derivative C2’epiAmB was synthesized with two different routes. This compound was confirmed to only bind ergosterol but not cholesterol. As a result, C2’epiAmB showed good potency to fungal cells but not human cells.Comprehensive experiments were completed to validate its safety profile and it showed superior efficacy in a mice disease model. Meanwhile, C2’epiAmB displayed reduced potency in several strains when compared with AmB. We systematically examined this difference and found that the ergosterol extraction rate primarily determines the potency, further elucidating our sterol sponge mechanism. With the sterol sponge mechanism established in AmB, the investigation of other glycosylated polyene macrolides’(GPM) mode of action was also performed. A highly conserved substructure among this class of natural products was utilized to expand GPM biosynthetic gene clusters (BGC). Kineosporicin, a first reported methyltetraene natural product, was discovered enabled by BGC analysis. This newly discovered GPM and other representative GPMs from different classes were further tested and confirmed that the sterol sponge mechanism was conserved in the GPM family. In addition, the ergosterol extraction mechanism was validated in leishmaniasis by using two AmB urea derivatives, AmB methyl urea (AmB-MU) and ethyl amino urea (AmB-AU). AmB-MU was also found well-tolerated and more effective when compared to AmB in a mice model. These studies demonstrated that besides looking at different formulations of AmB, derivatizing AmB could be an important way to improve its therapeutics in this prevalent disease. Lastly, we discovered a renal-sparing, fungicidal AmB derivative with combining the toxicity-eliminating C2’ modification and potency-increasing modification at C41 enabled by accelerating the ergosterol extraction rate. For the first time, this new derivative AM-2-19 achieved eradication of fungal infections in mice without causing toxicity. It is an up-and-coming drug candidate to help millions of patients."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/115675"],"dc:language":["en","eng"],"dc:rights":["Jiabao Zhang owns the copyright of this dissertation."],"dc:subject":["AmB","ergosterol","sterol sponge"],"dc:title":["Amphotericin B extracts ergosterol faster than fungi can make it"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:24:54Z"}