{"id":{"repo_id":"qu-belfast","oai_identifier":"oai:pure.qub.ac.uk/portal:studenttheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c"},"canonical_url":"https://search.dev.ndltd.org/etd/qu-belfast/oai:pure.qub.ac.uk/portal:studenttheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c","repository":{"repo_id":"qu-belfast","name":"Queen's University Belfast","base_url":"https://pureadmin.qub.ac.uk/ws/oai"},"display":{"title":"Structural and mechanistic studies on antimicrobial peptides that target multi-drug resistant bacteria","abstract":"Antimicrobial resistance is a growing threat that will have profound effects on global health and the economy. In order to avoid a worst-case scenario, there is a need to develop structurally distinct classes of antibiotics. Herein, the synthesis of cyclic lipopeptides based on the tridecaptins is reported. In particular, analogues where residues D-Trp5 and Phe9 were substituted for D-Cys and Cys respectively were synthesized and cross-linked with various benzylic linkers of various sizes. Ortho-xylyl, meta-xylyl and para-xylyl cross-linked Oct-TriA1 maintained strong activity against Escherichia coli and other ESKAPE pathogens (including carbapenem-resistant Acinetobacter baumannii). Interestingly, these analogues were resistant to enzymatic degradation in the presence of recently reported D-stereoselective peptidases. <br/><br/>Secondly, brevicidine represents a promising candidate for further research and development and this ultimately relies on a synthetic route to acquire sufficient material. The first reported synthesis of brevicidine is reported within this thesis. Briefly, an on-resin approach was used to pre-form the sensitive macrocyclic ring with a modified Yamaguchi esterification. Subsequent Fmoc-SPPS and global cleavage yielded the desired peptide in impressively high yields. With a synthetic route in hand, early structure-activity relationship studies were commenced. Subtle alterations did not ablate the antimicrobial activity while theoretically stabilizing the peptide towards in vivo hydrolysis.<br/><br/>Finally, attempts were made to synthesize various lipid tails to install on the depsipeptide globomycin. The natural and non-allo versions of linear globomycin were synthesized and tested using a recently developed fluorescence resonance energy transfer (FRET) assay developed by the Caffrey group.","abstract_html":"Antimicrobial resistance is a growing threat that will have profound effects on global health and the economy. In order to avoid a worst-case scenario, there is a need to develop structurally distinct classes of antibiotics. Herein, the synthesis of cyclic lipopeptides based on the tridecaptins is reported. In particular, analogues where residues D-Trp5 and Phe9 were substituted for D-Cys and Cys respectively were synthesized and cross-linked with various benzylic linkers of various sizes. Ortho-xylyl, meta-xylyl and para-xylyl cross-linked Oct-TriA1 maintained strong activity against Escherichia coli and other ESKAPE pathogens (including carbapenem-resistant Acinetobacter baumannii). Interestingly, these analogues were resistant to enzymatic degradation in the presence of recently reported D-stereoselective peptidases. &lt;br/&gt;&lt;br/&gt;Secondly, brevicidine represents a promising candidate for further research and development and this ultimately relies on a synthetic route to acquire sufficient material. The first reported synthesis of brevicidine is reported within this thesis. Briefly, an on-resin approach was used to pre-form the sensitive macrocyclic ring with a modified Yamaguchi esterification. Subsequent Fmoc-SPPS and global cleavage yielded the desired peptide in impressively high yields. With a synthetic route in hand, early structure-activity relationship studies were commenced. Subtle alterations did not ablate the antimicrobial activity while theoretically stabilizing the peptide towards in vivo hydrolysis.&lt;br/&gt;&lt;br/&gt;Finally, attempts were made to synthesize various lipid tails to install on the depsipeptide globomycin. The natural and non-allo versions of linear globomycin were synthesized and tested using a recently developed fluorescence resonance energy transfer (FRET) assay developed by the Caffrey group.","abstract_has_math":false,"creators":["Ballantine, Ross"],"institution":"Queen's University Belfast","degree_name":"Doctor of Philosophy","degree_level":"Doctoral Thesis","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Cochrane, Stephen","Stevenson, Paul"],"committee_chairs":[],"committee_members":[],"year":2021,"date_issued":"2021-7","date_published":"2021-7","updated_at":"2026-07-24T03:55:58Z","subjects":["Antimicrobial peptides","lipopeptides","antimicrobial resistance","peptides"],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:pure.qub.ac.uk/portal:studenttheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c"],"render_values":[{"text":"oai:pure.qub.ac.uk/portal:studenttheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c","href":null,"code":true}]}]},"links":{"outbound_url":"https://pure.qub.ac.uk/en/studentTheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Cochrane, Stephen","Stevenson, Paul"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Northern Ireland Department for the Economy"]},{"key":"dc:creator","label":"Author","values":["Ballantine, Ross"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2021-7"]},{"key":"dc:date.issued","label":"Date","values":["2021-7"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["School of Chemistry and Chemical Engineering"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["Queen's University Belfast"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://pure.qub.ac.uk/en/studentTheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral Thesis"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Antimicrobial peptides","lipopeptides","antimicrobial resistance","peptides"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2023-07-31"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:pure.qub.ac.uk/portal:studenttheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c","https://pure.qub.ac.uk/en/studentTheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://pure.qub.ac.uk/files/241310403/Structural_and_mechanistic_studies_on_antimicrobial_peptides_that_target_multi_drug_resistant.pdf","https://pure.qub.ac.uk/files/241374221/Structural_and_mechanistic_studies_on_antimicrobial_peptides_that_target_multi_drug_resistant.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Antimicrobial resistance is a growing threat that will have profound effects on global health and the economy. In order to avoid a worst-case scenario, there is a need to develop structurally distinct classes of antibiotics. Herein, the synthesis of cyclic lipopeptides based on the tridecaptins is reported. In particular, analogues where residues D-Trp5 and Phe9 were substituted for D-Cys and Cys respectively were synthesized and cross-linked with various benzylic linkers of various sizes. Ortho-xylyl, meta-xylyl and para-xylyl cross-linked Oct-TriA1 maintained strong activity against Escherichia coli and other ESKAPE pathogens (including carbapenem-resistant Acinetobacter baumannii). Interestingly, these analogues were resistant to enzymatic degradation in the presence of recently reported D-stereoselective peptidases. <br/><br/>Secondly, brevicidine represents a promising candidate for further research and development and this ultimately relies on a synthetic route to acquire sufficient material. The first reported synthesis of brevicidine is reported within this thesis. Briefly, an on-resin approach was used to pre-form the sensitive macrocyclic ring with a modified Yamaguchi esterification. Subsequent Fmoc-SPPS and global cleavage yielded the desired peptide in impressively high yields. With a synthetic route in hand, early structure-activity relationship studies were commenced. Subtle alterations did not ablate the antimicrobial activity while theoretically stabilizing the peptide towards in vivo hydrolysis.<br/><br/>Finally, attempts were made to synthesize various lipid tails to install on the depsipeptide globomycin. The natural and non-allo versions of linear globomycin were synthesized and tested using a recently developed fluorescence resonance energy transfer (FRET) assay developed by the Caffrey group."]},{"key":"dc:title","label":"Title","values":["Structural and mechanistic studies on antimicrobial peptides that target multi-drug resistant bacteria"]}]}],"canonical_facts":{"dc:contributor.advisor":["Cochrane, Stephen","Stevenson, Paul"],"dc:contributor.sponsor":["Northern Ireland Department for the Economy"],"dc:creator":["Ballantine, Ross"],"dc:date":["2021-7"],"dc:date.issued":["2021-7"],"dc:description.abstract":["Antimicrobial resistance is a growing threat that will have profound effects on global health and the economy. In order to avoid a worst-case scenario, there is a need to develop structurally distinct classes of antibiotics. Herein, the synthesis of cyclic lipopeptides based on the tridecaptins is reported. In particular, analogues where residues D-Trp5 and Phe9 were substituted for D-Cys and Cys respectively were synthesized and cross-linked with various benzylic linkers of various sizes. Ortho-xylyl, meta-xylyl and para-xylyl cross-linked Oct-TriA1 maintained strong activity against Escherichia coli and other ESKAPE pathogens (including carbapenem-resistant Acinetobacter baumannii). Interestingly, these analogues were resistant to enzymatic degradation in the presence of recently reported D-stereoselective peptidases. <br/><br/>Secondly, brevicidine represents a promising candidate for further research and development and this ultimately relies on a synthetic route to acquire sufficient material. The first reported synthesis of brevicidine is reported within this thesis. Briefly, an on-resin approach was used to pre-form the sensitive macrocyclic ring with a modified Yamaguchi esterification. Subsequent Fmoc-SPPS and global cleavage yielded the desired peptide in impressively high yields. With a synthetic route in hand, early structure-activity relationship studies were commenced. Subtle alterations did not ablate the antimicrobial activity while theoretically stabilizing the peptide towards in vivo hydrolysis.<br/><br/>Finally, attempts were made to synthesize various lipid tails to install on the depsipeptide globomycin. The natural and non-allo versions of linear globomycin were synthesized and tested using a recently developed fluorescence resonance energy transfer (FRET) assay developed by the Caffrey group."],"dc:identifier":["oai:pure.qub.ac.uk/portal:studenttheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c","https://pure.qub.ac.uk/en/studentTheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c"],"dc:identifier.uri":["https://pure.qub.ac.uk/files/241310403/Structural_and_mechanistic_studies_on_antimicrobial_peptides_that_target_multi_drug_resistant.pdf","https://pure.qub.ac.uk/files/241374221/Structural_and_mechanistic_studies_on_antimicrobial_peptides_that_target_multi_drug_resistant.pdf"],"dc:language":["eng"],"dc:publisher.department":["School of Chemistry and Chemical Engineering"],"dc:publisher.institution":["Queen's University Belfast"],"dc:relation.isreferencedby":["https://pure.qub.ac.uk/en/studentTheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c"],"dc:rights.embargodate":["2023-07-31"],"dc:subject":["Antimicrobial peptides","lipopeptides","antimicrobial resistance","peptides"],"dc:title":["Structural and mechanistic studies on antimicrobial peptides that target multi-drug resistant bacteria"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral Thesis"],"dc:type.qualificationname":["Doctor of Philosophy"]},"updated_at":"2026-07-24T03:55:58Z"}