Cell-based screening strategy in the search for bioactive microbial secondary metabolites

Iwasaki, Shigeo; Ōmura, Satoshi

doi:10.2183/pjab.80.54

Cited by 3 publications

(1 citation statement)

References 116 publications

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“…Morphological deformation of fungal hyphae is often induced by antifungal drugs [3]. As this phenomenon is specific to fungi, it could be used to screen for selective antifungal antibiotics [4]. In addition, this hyphal deformation is expected to reflect the disruption of cell wall biosynthesis, which is a specific target of antifungal agents.…”

Section: Introductionmentioning

confidence: 99%

Identification of Phoslactomycin E as a Metabolite Inducing Hyphal Morphological Abnormalities in Aspergillus fumigatus IFO 5840

et al. 2007

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In our survey for antifungal compounds, a fermentation broth of Streptomyces sp. HA81-2 was found to inhibit the in vitro growth of Aspergillus fumigatus IFO 5840 accompanied by hyphal morphological abnormalities. One of the isolated antibiotics was identified as phoslactomycin E based on LC-MS and NMR spectral data. In a preliminary assay using the membrane fractions of A. fumigatus, phoslactomycin E was found to inhibit the activity of 1,3-b glucan synthase.Keywords antifungal activity, phoslactomycin E, Aspergillus fumigatus, hyphal morphological abnormalities, 1,3-b glucan synthase Opportunistic fungal infections are a major cause of serious morbidity and mortality in immunocompromised patients. However, there are few drugs for antifungal chemotherapy of deep-seated mycosis. As both human and fungal cells are eukaryotes, it is difficult to develop antifungal drugs without side effects in human hosts. Current targets are limited to ergosterol, cell wall components, biosynthetic pathways of cell wall and cytosine deaminase [1,2]. Therefore, there is a great need for novel antifungal drugs with new mechanisms of action. Morphological deformation of fungal hyphae is often induced by antifungal drugs [3]. As this phenomenon is specific to fungi, it could be used to screen for selective antifungal antibiotics [4]. In addition, this hyphal deformation is expected to reflect the disruption of cell wall biosynthesis, which is a specific target of antifungal agents. Moreover, investigating the mechanism of antifungal-induced hyphal morphological abnormalities is potentially useful for understanding the morphogenesis of fungal hyphae.In the course of our search for antifungal antibiotics, we found that a fermentation broth of Streptomyces sp. HA81-2 exhibited antifungal activity against Aspergillus fumigatus IFO 5840 accompanied by hyphal abnormalities. The isolated active fraction was identified as phoslactomycin E (PLME) [5] based on LC-MS and NMR spectral data. We herein report the isolation procedures for PLME, its molecular characteristics, and its induction of morphological changes in fungal cells.Active principles were isolated as follows; fermentation broth was filtered, the filtrate was applied on Diaion HP-20 column, and then eluted using an increasing gradient of aq MeOH (10ϳ100%). The 80ϳ90% MeOH fractions were concentrated in vacuo to afford crude extract, which was partitioned between water and CHCl 3 . Purification of

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Section: Introductionmentioning

confidence: 99%

Identification of Phoslactomycin E as a Metabolite Inducing Hyphal Morphological Abnormalities in Aspergillus fumigatus IFO 5840

et al. 2007

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Tandem intramolecular benzyne–furan cycloadditions. Total synthesis of vineomycinone B2 methyl ester

2007

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We have exploited tandem intramolecular benzyne-furan cycloadditions employing three different benzyne precursors to generate substituted bisoxabenzonorbornadienes in a single operation. The regiochemical outcomes in these Diels-Alder reactions were effectively controlled by using disposable silicon tethers to link the reacting benzynes and furan moieties. Two different methods for converting the intermediate bisoxabenzonorbornadienes to substituted anthrarufins were developed. The first tactic entails the initial cleavage of the silicon tethers followed by regioselective ring opening of the oxabicycloheptadienes and oxidation of the central ring giving the target anthrarufin, whereas the second features the regioselective ring opening of the oxabicycloheptadienes followed by protiodesilylation and oxidation. When the starting furans bear carbohydrate substitutents, this new methodology enables the rapid assembly of the glycosyl-substituted aromatic cores of complex C-aryl glycoside antibiotics from simple starting materials. The utility of this novel approach to anthrarufins and C-aryl glycosides is exemplified in a triply convergent synthesis of vineomycinone B(2) methyl ester.

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Microbial metabolites: 45 years of wandering, wondering and discovering

Ōmura

2011

Tetrahedron

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Cell-based screening strategy in the search for bioactive microbial secondary metabolites

Cited by 3 publications

References 116 publications

Identification of Phoslactomycin E as a Metabolite Inducing Hyphal Morphological Abnormalities in Aspergillus fumigatus IFO 5840

Identification of Phoslactomycin E as a Metabolite Inducing Hyphal Morphological Abnormalities in Aspergillus fumigatus IFO 5840

Tandem intramolecular benzyne–furan cycloadditions. Total synthesis of vineomycinone B2 methyl ester

Microbial metabolites: 45 years of wandering, wondering and discovering

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