{"id":{"repo_id":"mit","oai_identifier":"oai:dspace.mit.edu:1721.1/109675"},"canonical_url":"https://search.dev.ndltd.org/etd/mit/oai:dspace.mit.edu:1721.1/109675","repository":{"repo_id":"mit","name":"MIT","base_url":"https://dspace.mit.edu/oai/request"},"display":{"title":"Synthesis of staphyloferrin B (SB)-cargo conjugates","abstract":"The ability of the Gram-positive human pathogen Staphylococcus aureus to cause infection and develop antimicrobial resistance poses a significant threat to public health. One potential method to combat bacterial infections involves the use of siderophore-drug conjugates to selectively deliver antibiotics to bacteria. Siderophores are low-molecular-weight chelators with high affinity for iron(Ill) that are biosynthesized by bacteria to acquire iron from the environment. Several reports of siderophore-mediated delivery of antibiotics to Gram-negative bacteria have been published. However, only a few examples of applying this strategy to Gram-positive bacteria are reported. Here, the potential of staphyloferrin B (SB), a polycarboxylate siderophore and virulence factor biosynthesized by S. aureus, for siderophore-drug conjugates is considered. In this thesis, the design and synthesis of a monofunctionalized SB scaffold in which the siderophore is site-electively modified with a polyethyleneglycol (PEG 3) linker and an azide moiety as a chemical handle is presented. The total synthesis of the monofunctionalized SB scaffold in 17 steps starting from 5 commercially available starting materials is reported. This molecule was employed to prepare a family of three SB-cargo conjugates using copper-catalyzed Click chemistry. In future work, these molecules can be used to probe the extent to which the S. aureus ferric-SB uptake and processing machinery recognizes, transports, and utilizes the derivatized SB scaffolds. Moreover, different antibiotics can be conjugated to SB and the effect on antimicrobial activity can be assessed.","abstract_html":"The ability of the Gram-positive human pathogen Staphylococcus aureus to cause infection and develop antimicrobial resistance poses a significant threat to public health. One potential method to combat bacterial infections involves the use of siderophore-drug conjugates to selectively deliver antibiotics to bacteria. Siderophores are low-molecular-weight chelators with high affinity for iron(Ill) that are biosynthesized by bacteria to acquire iron from the environment. Several reports of siderophore-mediated delivery of antibiotics to Gram-negative bacteria have been published. However, only a few examples of applying this strategy to Gram-positive bacteria are reported. Here, the potential of staphyloferrin B (SB), a polycarboxylate siderophore and virulence factor biosynthesized by S. aureus, for siderophore-drug conjugates is considered. In this thesis, the design and synthesis of a monofunctionalized SB scaffold in which the siderophore is site-electively modified with a polyethyleneglycol (PEG 3) linker and an azide moiety as a chemical handle is presented. The total synthesis of the monofunctionalized SB scaffold in 17 steps starting from 5 commercially available starting materials is reported. This molecule was employed to prepare a family of three SB-cargo conjugates using copper-catalyzed Click chemistry. In future work, these molecules can be used to probe the extent to which the S. aureus ferric-SB uptake and processing machinery recognizes, transports, and utilizes the derivatized SB scaffolds. Moreover, different antibiotics can be conjugated to SB and the effect on antimicrobial activity can be assessed.","abstract_has_math":false,"creators":["Gulati, Anmol"],"institution":"Massachusetts Institute of Technology","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Massachusetts Institute of Technology. Department of Chemistry.","school":null,"contributors":[],"advisors":["Elizabeth M. Nolan."],"committee_chairs":[],"committee_members":[],"year":2017,"date_issued":"2017","date_published":"2017","updated_at":"2026-07-22T22:21:48Z","subjects":["Chemistry."],"languages":["eng"],"rights":["MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission."],"rights_urls":["http://dspace.mit.edu/handle/1721.1/7582"],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1721.1/109675","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Elizabeth M. Nolan."]},{"key":"dc:contributor.department","label":"Department","values":["Massachusetts Institute of Technology. Department of Chemistry."]},{"key":"dc:contributor.other","label":"Dc Contributor Other","values":["Massachusetts Institute of Technology. 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One potential method to combat bacterial infections involves the use of siderophore-drug conjugates to selectively deliver antibiotics to bacteria. Siderophores are low-molecular-weight chelators with high affinity for iron(Ill) that are biosynthesized by bacteria to acquire iron from the environment. Several reports of siderophore-mediated delivery of antibiotics to Gram-negative bacteria have been published. However, only a few examples of applying this strategy to Gram-positive bacteria are reported. Here, the potential of staphyloferrin B (SB), a polycarboxylate siderophore and virulence factor biosynthesized by S. aureus, for siderophore-drug conjugates is considered. In this thesis, the design and synthesis of a monofunctionalized SB scaffold in which the siderophore is site-electively modified with a polyethyleneglycol (PEG 3) linker and an azide moiety as a chemical handle is presented. The total synthesis of the monofunctionalized SB scaffold in 17 steps starting from 5 commercially available starting materials is reported. This molecule was employed to prepare a family of three SB-cargo conjugates using copper-catalyzed Click chemistry. In future work, these molecules can be used to probe the extent to which the S. aureus ferric-SB uptake and processing machinery recognizes, transports, and utilizes the derivatized SB scaffolds. Moreover, different antibiotics can be conjugated to SB and the effect on antimicrobial activity can be assessed."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["S.M."]},{"key":"dc:title","label":"Title","values":["Synthesis of staphyloferrin B (SB)-cargo conjugates"]}]}],"canonical_facts":{"dc:contributor.advisor":["Elizabeth M. Nolan."],"dc:contributor.department":["Massachusetts Institute of Technology. Department of Chemistry."],"dc:contributor.other":["Massachusetts Institute of Technology. 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However, only a few examples of applying this strategy to Gram-positive bacteria are reported. Here, the potential of staphyloferrin B (SB), a polycarboxylate siderophore and virulence factor biosynthesized by S. aureus, for siderophore-drug conjugates is considered. In this thesis, the design and synthesis of a monofunctionalized SB scaffold in which the siderophore is site-electively modified with a polyethyleneglycol (PEG 3) linker and an azide moiety as a chemical handle is presented. The total synthesis of the monofunctionalized SB scaffold in 17 steps starting from 5 commercially available starting materials is reported. This molecule was employed to prepare a family of three SB-cargo conjugates using copper-catalyzed Click chemistry. In future work, these molecules can be used to probe the extent to which the S. aureus ferric-SB uptake and processing machinery recognizes, transports, and utilizes the derivatized SB scaffolds. 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