Muhammad Bilal Hassan Mahboob, Santhni Subramaniam, Jessica R. Tait, James L. Grace, Alysha G. Elliott, Holly Floyd, Johannes Zuegg, John F. Quinn, Clive A. Prestidge, Cornelia B. Landersdorfer and Michael R. Whittaker
{"title":"胆固醇封端阳离子脂化低聚物(CLOs)作为一种新型抗真菌药物。","authors":"Muhammad Bilal Hassan Mahboob, Santhni Subramaniam, Jessica R. Tait, James L. Grace, Alysha G. Elliott, Holly Floyd, Johannes Zuegg, John F. Quinn, Clive A. Prestidge, Cornelia B. Landersdorfer and Michael R. Whittaker","doi":"10.1039/D4TB02317J","DOIUrl":null,"url":null,"abstract":"<p >Infections caused by fungal pathogens are a global health problem, and have created an urgent need for new antimicrobial strategies. This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers <em>via</em> an optimized Cu(0)-mediated reversible-deactivation radical polymerization (RDRP) approach. Cholesterol-Br was used as an initiator to synthesize a library of oligo-VDM (degree of polymerisation = 5, 10, 15, 20, and 25), with an α-terminal cholesterol group. Subsequent ring-opening of the pendant oxazolone group with various functional amines [<em>i.e.</em>, 2-(2-aminoethyl)-1,3-di-Boc-guanidine (BG), 1-(3-aminopropyl)imidazole (IMID), <em>N</em>-Boc-ethylenediamine (BEDA), or <em>N</em>,<em>N</em>-dimethylethylenediamine (DMEN)] yielded an 11 functional cationic lipidated oligomer (CLOs) library, which comprised different cationic elements with the same terminal lipid cholesterol element. These CLOs exhibited greater activity against all tested fungal pathogens (<em>Candida albicans</em>, <em>Cryptococcus neoformans</em>, <em>Candida tropicalis</em>, <em>Candida glabrata</em>, <em>Cryptococcus deuterogattii</em>, and <em>Candida auris</em>), compared to the bacterial pathogens (<em>Escherichia coli</em>, <em>Klebsiella pneumoniae</em>, <em>Acinetobacter baumannii</em>, <em>Pseudomonas aeruginosa</em> or methicillin-resistant <em>Staphylococcus aureus</em> [MRSA]). Specifically, the DMEN and BEDA (after deprotection) series exhibited superior antifungal activities 4–16 times greater [determined by the minimum inhibitory concentration (MIC) in μg mL<small><sup>−1</sup></small>] than the clinically relevant antifungal fluconazole. Two ‘hit’ CLOs (Chol-DMEN-25 and Chol-BEDA-10) were identified, which inhibited both single sp. (<em>C. albicans</em>, <em>C. tropicalis</em>, <em>C. neoformans</em>, or <em>C. gattii</em>) and dual sp. (<em>C. albicans</em> and <em>C. tropicalis</em>) biofilm formation, and were able to attenuate mature biofilms, with a >50% mature biofilm biomass reduction at 128 μg mL<small><sup>−1</sup></small>. Co-delivery of fluconazole with two ‘hit’ CLOs demonstrated additive and synergistic effects on the aforementioned single-species and dual-species fungi biofilms, with a synergy score (SS) ranging from ∼3 to 15 and most synergistic area score (MSAS) ∼13–29 (by a Bliss independence model). The mechanistic studies (PI assay and nucleic acid release assay) revealed that these CLOs disrupted the integrity of fungal cell membranes. These results demonstrate that cholesterol terminated CLOs are potential antifungal candidates.</p>","PeriodicalId":83,"journal":{"name":"Journal of Materials Chemistry B","volume":" 8","pages":" 2776-2795"},"PeriodicalIF":6.1000,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cholesterol-terminated cationic lipidated oligomers (CLOs) as a new class of antifungals†\",\"authors\":\"Muhammad Bilal Hassan Mahboob, Santhni Subramaniam, Jessica R. Tait, James L. Grace, Alysha G. Elliott, Holly Floyd, Johannes Zuegg, John F. Quinn, Clive A. Prestidge, Cornelia B. Landersdorfer and Michael R. Whittaker\",\"doi\":\"10.1039/D4TB02317J\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Infections caused by fungal pathogens are a global health problem, and have created an urgent need for new antimicrobial strategies. This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers <em>via</em> an optimized Cu(0)-mediated reversible-deactivation radical polymerization (RDRP) approach. Cholesterol-Br was used as an initiator to synthesize a library of oligo-VDM (degree of polymerisation = 5, 10, 15, 20, and 25), with an α-terminal cholesterol group. Subsequent ring-opening of the pendant oxazolone group with various functional amines [<em>i.e.</em>, 2-(2-aminoethyl)-1,3-di-Boc-guanidine (BG), 1-(3-aminopropyl)imidazole (IMID), <em>N</em>-Boc-ethylenediamine (BEDA), or <em>N</em>,<em>N</em>-dimethylethylenediamine (DMEN)] yielded an 11 functional cationic lipidated oligomer (CLOs) library, which comprised different cationic elements with the same terminal lipid cholesterol element. These CLOs exhibited greater activity against all tested fungal pathogens (<em>Candida albicans</em>, <em>Cryptococcus neoformans</em>, <em>Candida tropicalis</em>, <em>Candida glabrata</em>, <em>Cryptococcus deuterogattii</em>, and <em>Candida auris</em>), compared to the bacterial pathogens (<em>Escherichia coli</em>, <em>Klebsiella pneumoniae</em>, <em>Acinetobacter baumannii</em>, <em>Pseudomonas aeruginosa</em> or methicillin-resistant <em>Staphylococcus aureus</em> [MRSA]). Specifically, the DMEN and BEDA (after deprotection) series exhibited superior antifungal activities 4–16 times greater [determined by the minimum inhibitory concentration (MIC) in μg mL<small><sup>−1</sup></small>] than the clinically relevant antifungal fluconazole. Two ‘hit’ CLOs (Chol-DMEN-25 and Chol-BEDA-10) were identified, which inhibited both single sp. (<em>C. albicans</em>, <em>C. tropicalis</em>, <em>C. neoformans</em>, or <em>C. gattii</em>) and dual sp. (<em>C. albicans</em> and <em>C. tropicalis</em>) biofilm formation, and were able to attenuate mature biofilms, with a >50% mature biofilm biomass reduction at 128 μg mL<small><sup>−1</sup></small>. Co-delivery of fluconazole with two ‘hit’ CLOs demonstrated additive and synergistic effects on the aforementioned single-species and dual-species fungi biofilms, with a synergy score (SS) ranging from ∼3 to 15 and most synergistic area score (MSAS) ∼13–29 (by a Bliss independence model). The mechanistic studies (PI assay and nucleic acid release assay) revealed that these CLOs disrupted the integrity of fungal cell membranes. 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Cholesterol-terminated cationic lipidated oligomers (CLOs) as a new class of antifungals†
Infections caused by fungal pathogens are a global health problem, and have created an urgent need for new antimicrobial strategies. This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers via an optimized Cu(0)-mediated reversible-deactivation radical polymerization (RDRP) approach. Cholesterol-Br was used as an initiator to synthesize a library of oligo-VDM (degree of polymerisation = 5, 10, 15, 20, and 25), with an α-terminal cholesterol group. Subsequent ring-opening of the pendant oxazolone group with various functional amines [i.e., 2-(2-aminoethyl)-1,3-di-Boc-guanidine (BG), 1-(3-aminopropyl)imidazole (IMID), N-Boc-ethylenediamine (BEDA), or N,N-dimethylethylenediamine (DMEN)] yielded an 11 functional cationic lipidated oligomer (CLOs) library, which comprised different cationic elements with the same terminal lipid cholesterol element. These CLOs exhibited greater activity against all tested fungal pathogens (Candida albicans, Cryptococcus neoformans, Candida tropicalis, Candida glabrata, Cryptococcus deuterogattii, and Candida auris), compared to the bacterial pathogens (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus [MRSA]). Specifically, the DMEN and BEDA (after deprotection) series exhibited superior antifungal activities 4–16 times greater [determined by the minimum inhibitory concentration (MIC) in μg mL−1] than the clinically relevant antifungal fluconazole. Two ‘hit’ CLOs (Chol-DMEN-25 and Chol-BEDA-10) were identified, which inhibited both single sp. (C. albicans, C. tropicalis, C. neoformans, or C. gattii) and dual sp. (C. albicans and C. tropicalis) biofilm formation, and were able to attenuate mature biofilms, with a >50% mature biofilm biomass reduction at 128 μg mL−1. Co-delivery of fluconazole with two ‘hit’ CLOs demonstrated additive and synergistic effects on the aforementioned single-species and dual-species fungi biofilms, with a synergy score (SS) ranging from ∼3 to 15 and most synergistic area score (MSAS) ∼13–29 (by a Bliss independence model). The mechanistic studies (PI assay and nucleic acid release assay) revealed that these CLOs disrupted the integrity of fungal cell membranes. These results demonstrate that cholesterol terminated CLOs are potential antifungal candidates.
期刊介绍:
Journal of Materials Chemistry A, B & C cover high quality studies across all fields of materials chemistry. The journals focus on those theoretical or experimental studies that report new understanding, applications, properties and synthesis of materials. Journal of Materials Chemistry A, B & C are separated by the intended application of the material studied. Broadly, applications in energy and sustainability are of interest to Journal of Materials Chemistry A, applications in biology and medicine are of interest to Journal of Materials Chemistry B, and applications in optical, magnetic and electronic devices are of interest to Journal of Materials Chemistry C.Journal of Materials Chemistry B is a Transformative Journal and Plan S compliant. Example topic areas within the scope of Journal of Materials Chemistry B are listed below. This list is neither exhaustive nor exclusive:
Antifouling coatings
Biocompatible materials
Bioelectronics
Bioimaging
Biomimetics
Biomineralisation
Bionics
Biosensors
Diagnostics
Drug delivery
Gene delivery
Immunobiology
Nanomedicine
Regenerative medicine & Tissue engineering
Scaffolds
Soft robotics
Stem cells
Therapeutic devices