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1.
Nat Commun ; 11(1): 6058, 2020 11 27.
Article in English | MEDLINE | ID: mdl-33247171

ABSTRACT

Novel antibiotics are urgently needed to address the looming global crisis of antibiotic resistance. Historically, the primary source of clinically used antibiotics has been microbial secondary metabolism. Microbial genome sequencing has revealed a plethora of uncharacterized natural antibiotics that remain to be discovered. However, the isolation of these molecules is hindered by the challenge of linking sequence information to the chemical structures of the encoded molecules. Here, we present PRISM 4, a comprehensive platform for prediction of the chemical structures of genomically encoded antibiotics, including all classes of bacterial antibiotics currently in clinical use. The accuracy of chemical structure prediction enables the development of machine-learning methods to predict the likely biological activity of encoded molecules. We apply PRISM 4 to chart secondary metabolite biosynthesis in a collection of over 10,000 bacterial genomes from both cultured isolates and metagenomic datasets, revealing thousands of encoded antibiotics. PRISM 4 is freely available as an interactive web application at http://prism.adapsyn.com .


Subject(s)
Genome, Microbial , Secondary Metabolism/genetics , Anti-Bacterial Agents/pharmacology , Base Sequence , Biosynthetic Pathways/drug effects , Biosynthetic Pathways/genetics , Metagenomics , Multigene Family , Quantitative Structure-Activity Relationship , ROC Curve , Secondary Metabolism/drug effects , Support Vector Machine
2.
Chem Biodivers ; 16(3): e1800579, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30557446

ABSTRACT

Leaves of the plant species Isatis indigotica Fortune ex Lindl. (Chinese woad) produce the metabolites tryptanthrin, indirubin and N-formylanthranilic acid upon spraying with an aqueous solution of copper chloride but not after spraying with water. The antifungal activities of these metabolites against the phytopathogens Alternaria brassicicola, Leptosphaeria maculans and Sclerotinia sclerotiorum established that tryptanthrin is a much stronger growth inhibitor of L. maculans than the phytoalexin camalexin. The biosynthetic precursors of tryptanthrin and N-formylanthranilic acid are proposed based on the deuterium incorporations of isotopically labeled compounds. The overall results suggest that tryptanthrin is a phytoalexin and indirubin and N-formylanthranilic acid are phytoanticipins in the plant species I. indigotica and that chemical diversity and biodiversity are intimately connected.


Subject(s)
Alternaria/drug effects , Antifungal Agents/pharmacology , Ascomycota/drug effects , Drugs, Chinese Herbal/pharmacology , Isatis/chemistry , Quinazolines/pharmacology , ortho-Aminobenzoates/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/isolation & purification , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/isolation & purification , Indoles/chemistry , Indoles/isolation & purification , Indoles/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Quinazolines/chemistry , Quinazolines/isolation & purification , Structure-Activity Relationship , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/isolation & purification
3.
Org Biomol Chem ; 16(19): 3625-3638, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29708249

ABSTRACT

The discovery of the first non-indolyl cruciferous phytoalexins nasturlexins A and B together with cyclonasturlexin and brassinin, all chemical defenses of watercress plants (Nasturtium officinale R. Br.), revealed the co-occurrence of two parallel defense pathways, the tryptophan (Trp) pathway and the phenylalanine (Phe) pathway in crucifers. Similar to watercress, winter cress (Barbarea vulgaris R. Br.) and upland cress [B. verna (P. Mill.) Aschers] produce Phe derived phytoalexins, the nasturlexins C and D together with their counterpart sulfoxides. A detailed chemical understanding of the biosynthetic pathways of these phytoalexins facilitates their metabolic engineering. To this end, the biosynthetic pathways of cyclonasturlexin, nasturlexins A-D and corresponding sulfoxides in cress plants were investigated using isotopically labelled compounds. Except for the carbon atom of the thiomethyl groups of nasturlexins, the origin of all carbon atoms and nitrogen of nasturlexins was established to be homophenylalanine. A detailed map of the biosynthetic intermediates between phenylethyl isothiocyanates and nasturlexins A-D and sulfoxides in upland cress, winter cress and watercress is proposed. An application beyond these findings could lead to "designer crops" containing a wider range of chemical defenses that could make such crops more resistant to pests and diseases, a greatly advantageous trait.


Subject(s)
Brassicaceae/metabolism , Sesquiterpenes/metabolism , Brassicaceae/chemistry , Isotope Labeling , Plant Leaves/chemistry , Plant Leaves/metabolism , Phytoalexins
4.
J Labelled Comp Radiopharm ; 61(2): 94-106, 2018 02.
Article in English | MEDLINE | ID: mdl-29231250

ABSTRACT

The syntheses of perdeuterated phytoalexins nasturlexins A and C, and putative biosynthetic precursors, including phenylethyl isothiocyanates and phenylethyl dithiocarbamates, using commercially available [2,3,4,5,6-D5 ]phenylalanine, [2,3,4,5,6-D5 ]nitrobenzene, and [2,3,4,5,6-D5 ]benzaldehyde are described. In addition, application of an efficient deuterium-hydrogen exchange transformation to nonlabeled starting materials allowed access to new deuterated compounds, including 3-hydroxyphenylethyl glucosinolate.


Subject(s)
Deuterium/chemistry , Sesquiterpenes/chemistry , Glucosinolates/chemistry , Nitrobenzenes/chemistry , Phenylalanine/chemistry , Thiocarbamates/chemistry , Thiocyanates/chemistry , Phytoalexins
5.
Phytochemistry ; 139: 18-24, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28390240

ABSTRACT

Erucastrum canariense Webb & Berthel. (Brassicaceae) is a wild crucifer that grows in rocky soils, in salt and water stressed habitats, namely in the Canary Islands and similar environments. Abiotic stress induced by copper chloride triggered formation of a phytoalexin and galacto-oxylipins in E. canariense, whereas wounding induced galacto-oxylipins but not phytoalexins. Analysis of the metabolite profiles of leaves of E. canariense followed by isolation and structure determination afforded the phytoalexin erucalexin, the phytoanticipin indolyl-3-acetonitrile, the galacto-oxylipins arabidopsides A, C, and D, and the oxylipin 12-oxophytodienoic acid. In addition, arabidopsides A and D were also identified in extracts of leaves of Nasturtium officinale R. Br.


Subject(s)
Antifungal Agents/isolation & purification , Brassicaceae/chemistry , Oxylipins/metabolism , Sesquiterpenes/metabolism , Antifungal Agents/chemistry , Brassicaceae/growth & development , Chromatography, High Pressure Liquid , Fatty Acids, Unsaturated/chemistry , Fatty Acids, Unsaturated/metabolism , Indoles/analysis , Indoles/chemistry , Indoles/isolation & purification , Molecular Structure , Nasturtium/chemistry , Nuclear Magnetic Resonance, Biomolecular , Plant Leaves/chemistry , Sesquiterpenes/pharmacology , Spain , Spiro Compounds/analysis , Spiro Compounds/chemistry , Spiro Compounds/isolation & purification , Thiazoles/analysis , Thiazoles/chemistry , Thiazoles/isolation & purification , Time Factors , Phytoalexins
6.
Phytochemistry ; 118: 131-8, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26318326

ABSTRACT

The metabolites produced in leaves of the crucifers winter cress (Barbarea vulgaris) and upland cress (Barbarea verna) abiotically elicited were investigated and their chemical structures were elucidated by analyses of spectroscopic data and confirmed by syntheses. Nasturlexins C and D and their sulfoxides are cruciferous phytoalexins displaying antifungal activity against the crucifer pathogens Alternaria brassicicola, Leptosphaeria maculans and Sclerotinia sclerotiorum. The biosynthesis of these metabolites is proposed based on pathways of cruciferous indolyl phytoalexins. This work indicates that B. vulgaris and B. verna have great potential as sources of defense pathways transferable to agriculturally important crops within the Brassica species.


Subject(s)
Barbarea/chemistry , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Sulfoxides/isolation & purification , Alternaria/metabolism , Antifungal Agents/chemistry , Ascomycota/metabolism , Brassica/metabolism , Nuclear Magnetic Resonance, Biomolecular , Plant Leaves/chemistry , Sesquiterpenes/pharmacology , Sulfoxides/chemistry , Sulfoxides/pharmacology , Phytoalexins
7.
Phytochemistry ; 113: 57-63, 2015 May.
Article in English | MEDLINE | ID: mdl-25152450

ABSTRACT

Highly specialized chemical defense pathways are a particularly noteworthy metabolic characteristic of sessile organisms, whether terrestrial or marine, providing protection against pests and diseases. For this reason, knowledge of the metabolites involved in these processes is crucial to producing ecologically fit crops. Toward this end, the elicited chemical defenses of the crucifer watercress (Nasturtium officinale R. Br.), i.e. phytoalexins, were investigated and are reported. Almost three decades after publication of cruciferous phytoalexins derived from (S)-Trp, phytoalexins derived from other aromatic amino acids were isolated; their chemical structures were determined by analyses of their spectroscopic data and confirmed by synthesis. Nasturlexin A, nasturlexin B, and tridentatol C are hitherto unknown phenyl containing cruciferous phytoalexins produced by watercress under abiotic stress; tridentatol C is also produced by a marine animal (Tridentata marginata), where it functions in chemical defense against predators. The biosynthesis of these metabolites in both a terrestrial plant and a marine animal suggests a convergent evolution of unique metabolic pathways recruited for defense.


Subject(s)
Nasturtium/physiology , Sesquiterpenes , Animals , Brassicaceae/chemistry , Chromatography, High Pressure Liquid , Marine Biology , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Phenols , Seeds/chemistry , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Sesquiterpenes/metabolism , Tryptophan/chemistry , Phytoalexins
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