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Journal Articles - UP - MSI

Permanent URI for this collectionhttps://repository.unesco.gov.ph/handle/123456789/50

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    Genomic and targeted approaches unveil the cell membrane as a major target of the antifungal cytotoxin amantelide A
    Elsadek, Lobna A.; Matthews, James H.; Nishimura, Shinichi; Nakatani, Takahiro; Ito, Airi; Gu, Tongjun; Luo, Danmeng; Salvador-Reyes, Lilibeth A.; Paul, Valerie J.; Kakeya, Hideaki; Luesch, Hendrik (Wiley, 2021-03-23)
    Amantelide A, a polyhydroxylated macrolide isolated from a marine cyanobacterium, displays broad-spectrum activity against mammalian cells, bacterial pathogens, and marine fungi. We conducted comprehensive mechanistic studies to identify the molecular targets and pathways affected by amantelide A. Our investigations relied on chemical structure similarities with compounds of known mechanisms, yeast knockout mutants, yeast chemogenomic profiling, and direct biochemical and biophysical methods. We established that amantelide A exerts its antifungal action by binding to ergosterol-containing membranes followed by pore formation and cell death, a mechanism partially shared with polyene antifungals. Binding assays demonstrated that amantelide A also binds to membranes containing epicholesterol or mammalian cholesterol, thus suggesting that the cytotoxicity to mammalian cells might be due to its affinity to cholesterol-containing membranes. However, membrane interactions were not completely dependent on sterols. Yeast chemogenomic profiling suggested additional direct or indirect effects on actin. Accordingly, we performed actin polymerization assays, which suggested that amantelide A also promotes actin polymerization in cell-free systems. However, the C-33 acetoxy derivative amantelide B showed a similar effect on actin dynamics in vitro but no significant activity against yeast. Overall, these studies suggest that the membrane effects are the most functionally relevant for amantelide A mechanism of action.
    This research was supported by the National Institutes of Health (grant R01CA172310 to H.L.), the Debbie and Sylvia DeSantis Chair Professorship (H.L), and a Grant-in Aid for Scientific Research (no. 17H06401 to S.N. and H.K.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. L.E. was supported by the NIH/NIGMS T32GM136583 “Chemistry-Biology Interface Training Program at the University of Florida”. We thank Dr. Yanping Zhang (University of Florida) from the UF ICBR NextGen DNA Sequencing core facility for carrying out the nextgeneration sequencing, Dr. Maya Schuldiner (Weizmann Institute of Science, Israel) for providing the triple yeast deletion library, Dr. Kaoru Takegawa (Kyushu University, Japan) for providing the ergosterol mutants, Dr. Charles Boone laboratory (University of Toronto, Canada) for providing the wild-type S. cerevisiae Y7092 and Dr. Kalina Atanasova (CNPD3, University of Florida) for assistance with the imaging.
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    Total synthesis and bioactivity evaluation of hydrophobic microcionamide‐inspired peptides
    Inocentes, Carl Rogel V.; Salvador‐Reyes, Lilibeth A.; Villaraza, Aaron Joseph L. (Wiley, 2023-01)
    In this report, we describe the facile synthesis of four microcionamide-inspired peptides where the atypical 2-phenylethylenamine (2-PEA) functional group in the marine natural product, microcionamide A, was replaced with a similarly-aromatic but more easily incorporated tryptophan (Trp) residue. Compounds 1–4 were synthesized using a standard Fmoc-based solid-phase synthesis strategy followed by iodine-mediated on-resin cyclization for disulfide-bridged compounds 1–3. Compound 1 showed antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa, with minimum inhibitory concentrations (MICs) of 9.1 μM and 15 μM, respectively. The inactivity of alanine analogs 2–4 against these pathogens suggests that the N-terminal Val, the cyclic scaffold, the contiguous Ile residues, and consequently, the hydrophobicity of compound 1 are essential for antibacterial activity. Compound 1 also favorably exhibited minimal cytotoxicity against normal mammalian cell lines. In summary, we have synthesized an analog of microcionamide A where replacement of the 2-PEA moiety with a Trp residue retained the antibacterial activity and with favorably low cytotoxicity.