Aureobasidin A (AbA) is a novel cyclic depsipeptide antifungal antibiotic. The antifungal activity of AbAwas studied in vitro and in vivo in comparison with clinically effective antifungal agents, amphotericin B and fluconazole. AbAwas highly active in vitro against many pathogenic fungi, including Candida albicans, Cryptococcus neoformans, Blastomyces dermatitidis and Histoplasma capsulatum. The activity was superior to amphotericin B in most cases. AbAexhibited fungicidal action toward growing cultures of C. albicans. It was highly tolerated by mice and showed good efficacy in the treatment of murine systemic candidiasis whengiven orally or subcutaneously. AbA's fungicidal action in mice with candidiasis was more effective than fluconazole and amphotericin B.The incidence of systemic fungal infections are increasing in immunecompromisedpatients with several underlying diseases, such as leukemia and acquired immunodeficiency syndrome (AIDS), and in patients receiving anti-neoplastic agents, immunosuppressive agents or broad spectrum antibacterial antibiotics. Amphotericin B, flucytosine, and two imidazole drugs, miconazole and ketoconazole, have been the drugs of choice for systemic antifungal chemotherapy. Recently, two neworal triazoles, fluconazole and itraconazole,1) have been successfully developed and are now available for the treatment of some systemic fungal infections. However, clinical usefulness of all of these drugs is limited to insufficient therapeutic efficacy and/or toxicity. Thus there is a need for novel antifungal agents with a greater clinical efficacy.Aureobasidin A (AbA) is a new antifungal cyclic depsipeptide antibiotic (Fig. 1) produced by Aureobasidium pullulans R106.2~4) The characteristic of the structure of AbAis that of a peptide composed of eight L-form amino acids linked through one hydroxy acid to form a ring structure. There are some cyclic peptide antibiotics with antifungal activity in vitro, including valinomycin,5) syringomycin,6'7) calophycin8) and aculeacin/echinocandin family.9~1 1} Manyof them effect cell membrane permeability and have toxicity to eukaryotic cells. Several antifungal cyclic peptides with a long-chain fatty acid, such as aculeacin A, echinocandin B and their analogs, inhibit fungal cell wall synthesis with low acute toxicity. 9' 1 0) However, they show a narrow spectrum antifungal activity, ineffectiveness to murine candidiasis when given orally, and hemolytic effect. On the other hand, AbAhas a broader spectrum and higher
Aureobasidins A to R were isolated from the fermentation broth of Aureobasidium pullulans R106. Aureobasidins are cyclic depsipeptide antibiotics with MW's ranging from 1,070 to 1,148. Aureobasidins showed high in vitro antifungal activity against Candida albicans.
Purpose: Preparative lymphodepletion, the temporal ablation of the immune system, has been reported to promote persistence of transferred cells along with increased rates of tumor regression in patients treated with adoptive T-cell therapy. However, it remains unclear whether lymphodepletion is indispensable for immunotherapy with T-cell receptor (TCR) gene-engineered T cells.Experimental Design: We conducted a first-in-man clinical trial of TCR gene-transduced T-cell transfer in patients with recurrent MAGE-A4-expressing esophageal cancer. The patients were given sequential MAGE-A4 peptide vaccinations. The regimen included neither lymphocyte-depleting conditioning nor administration of IL2. Ten patients, divided into 3 dose cohorts, received T-cell transfer.Results: TCR-transduced cells were detected in the peripheral blood for 1 month at levels proportional to the dose administered, and in 5 patients they persisted for more than 5 months. The persisting cells maintained ex vivo antigen-specific tumor reactivity. Despite the long persistence of the transferred T cells, 7 patients exhibited tumor progression within 2 months after the treatment. Three patients who had minimal tumor lesions at baseline survived for more than 27 months.Conclusions: These results suggest that TCR-engineered T cells created by relatively short-duration in vitro culture of polyclonal lymphocytes in peripheral blood retained the capacity to survive in a host. The discordance between T-cell survival and tumor regression suggests that multiple mechanisms underlie the benefits of preparative lymphodepletion in adoptive T-cell therapy.
The human melanocyte lineage-specific antigen gp100 contains several epitopes recognized by cytotoxic T lymphocytes (CTL). However, most of the epitopes reported to date are HLA-A2.1-restricted. Despite the high frequency of HLA-A2.1 in melanoma patients, effective population coverage requires the identification of epitopes restricted by other frequent HLA alleles. Herein, HLA-A3 binding, gp100-derived synthetic peptides were tested for their capacity to elicit anti-melanoma CTL in vitro using CD8 ؉ T cells from healthy donors as responders and peptide-pulsed autologous dendritic cells as antigen-presenting cells. Of 7 peptides tested, 2 (gp100[9 87 ] and gp100[10 86 ] ) induced CTLs that killed melanoma cell lines expressing HLA-A3 and gp100. Additional MHC-binding studies to various HLA molecules belonging to the HLA-A3 superfamily (HLA-A*1101, -A*3101, -A*3301 and -A*6801) were performed to determine whether these CTL epitopes could further increase potential population coverage. Further experiments indicated that the peptide gp100[9 87 ], which bound to HLA-A11 with high affinity, was capable of inducing specific CTLs that killed melanoma cells expressing gp100 and HLA-A11 molecules. Our results indicate that the gp100[9 87 ] peptide corresponds to a CTL epitope which may be restricted by either the HLA-A3 or HLA-A11 allele, emphasizing its utility for the design and development of epitope-based therapies for melanoma. Int.
Aureobasidin A, an antifungal antibiotic inhibiting a wide range of pathogenic fungi, is lethal for growing cells of susceptible fungi. We did cytological studies on the mechanism of its fungicidal action against Saccharomyces cerevisiae. When cultures were treated with 5.0 micrograms of aureobasidin A per ml, the numbers of viable cells started to decrease after 2 to 3 h of incubation, and most cells had lost viability after 5 to 6 h. When cell death in the treated cultures began, amino acids released by the cells could be detected, indicating disruption of the cell membrane. The proportion of cells with a single small bud or two or more buds increased as the population of viable cells decreased. Most such cells had the DNA content of cells in the G2 phase of the cell cycle, suggesting that the drug inhibited some cellular process involved in normal bud growth but did not affect DNA replication. Disruption of actin assembly was found in many cells treated for 2 to 3 h, as was chitin delocalization. The results suggest that aureobasidin A has a previously unknown mechanism of fungicidal action toward S. cerevisiae. It causes aberrant actin assembly, inhibiting the normal budding process and leading to cell death, probably through destruction of membrane integrity.
Aureobasidin A, a new antifungal antibiotic, was isolated from the culture mediumof Aureobasidium pullulans R106. Aureobasidin A was a cyclic depsipeptide consisting of eight a-amino acid units and one hydroxy acid unit. The structures of the units were found by acid hydrolysis of the antibiotic to be 2 and L-phenyl-alanine. The sequence of the units was identified by NMRand FAB-MSof the products from the alkaline hydrolysis of aureobasidin A. 925Aureobasidins are complexes of antifungal antibiotics produced by Aureobasidium pullulans R106. The production, isolation, characterization, and antifungal activity of aureobasidins have been described in the preceding paper.1) In this paper, we report on the structure of aureobasidin A.Aureobasidin A (1, Fig. 1 The IR spectrum of 1 showed the presence of ester (1750cm"1) and amido carbonyls (1640cm"1). Mild alkaline hydrolysis (0.25 n NaOHin aqueous MeOH, room temperature, 25 hours) of 1 gave 2 and 3. Compounds 1 and 3 were negative in the ninhydrin color reaction and did not react with diazomethane or acetic anhydride in pyridine at room temperature. Compound 2 was also negative in the ninhydrin color reaction, but gave the methyl ester derivative 2a by treatment with diazomethane, and O-acetyl derivative 2b by treatment with acetic anhydride in pyridine. Further, 2a gave derivative 2c with O-acetyl and methyl ester groups when treated with acetic anhydride in pyridine.
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