Secondary metabolites of Alternaria: A comprehensive review of chemical diversity and pharmacological properties

Fungi are considered to be one of the wealthiest sources of bio-metabolites that can be employed for yielding novel biomedical agents. Alternaria, including parasitic, saprophytic, and endophytic species, is a kind of dark fungi that can produce a broad array of secondary metabolites (SMs) widely distributed in many ecosystems. These are categorized into polyketides, nitrogen-containing compounds, quinones, terpenes, and others based on the unique structural features of the metabolites. New natural products derived from Alternaria exhibit excellent bioactivities characterized by antibacterial, antitumor, antioxidative, phytotoxic, and enzyme inhibitory properties. Thus, the bio-metabolites of Alternaria species are significantly meaningful for pharmaceutical, industrial, biotechnological, and medicinal applications. To update the catalog of secondary metabolites synthesized by Alternaria fungi, 216 newly described metabolites isolated from Alternaria fungi were summarized with their diverse chemical structures, pharmacological activity, and possible biosynthetic pathway. In addition, possible insights, avenues, and challenges for future research and development of Alternaria are discussed.

[1]  Amer H. Asseri,et al.  Stachybotrys chartarum—A Hidden Treasure: Secondary Metabolites, Bioactivities, and Biotechnological Relevance , 2022, Journal of fungi.

[2]  H. Kalaji,et al.  Recent Advances in Alternaria Phytotoxins: A Review of Their Occurrence, Structure, Bioactivity, and Biosynthesis , 2022, Journal of fungi.

[3]  M. Shaaban,et al.  Diverse polyketides from the marine endophytic Alternaria sp. LV52: Structure determination and cytotoxic activities , 2021, Biotechnology reports.

[4]  G. Mohamed,et al.  Bright Side of Fusarium oxysporum: Secondary Metabolites Bioactivities and Industrial Relevance in Biotechnology and Nanotechnology , 2021, Journal of Fungi.

[5]  Weiguang Sun,et al.  New α-pyrone derivatives with herbicidal activity from the endophytic fungus Alternaria brassicicola. , 2021, Bioorganic chemistry.

[6]  B. Feng,et al.  Polyketone metabolites isolated from Rhodiola tibetica endohytic fungus Alternaria sp. HJT-Y7 and their SARS-CoV-2 virus inhibitory activitives , 2021, Bioorganic Chemistry.

[7]  Chong Liu,et al.  Trichoderma: A Treasure House of Structurally Diverse Secondary Metabolites With Medicinal Importance , 2021, Frontiers in Microbiology.

[8]  J. Zhang,et al.  Diverse anti-inflammation and anti-cancer polyketides isolated from the endophytic fungi Alternaria sp. MG1. , 2021, Fitoterapia.

[9]  G. Jiang,et al.  Alternaria Mycotoxins: An Overview of Toxicity, Metabolism, and Analysis in Food. , 2021, Journal of agricultural and food chemistry.

[10]  N. Jambari,et al.  Mycopharmaceuticals and Nutraceuticals: Promising Agents to Improve Human Well-Being and Life Quality , 2021, Journal of fungi.

[11]  Xu Li,et al.  Biotransformation of doxycycline by Brevundimonas naejangsanensis and Sphingobacterium mizutaii strains. , 2021, Journal of hazardous materials.

[12]  Y. Ye,et al.  Novel metabolites from the Cercis chinensis derived endophytic fungus Alternaria alternata ZHJG5 and their antibacterial activities. , 2021, Pest management science.

[13]  A. González-Coloma,et al.  Bioactive Metabolites from the Endophytic Fungus Aspergillus sp. SPH2 , 2020, Journal of fungi.

[14]  Y. Ye,et al.  Enantiomeric Dibenzo-α-Pyrone Derivatives from Alternaria alternata ZHJG5 and Their Potential as Agrochemicals. , 2020, Journal of agricultural and food chemistry.

[15]  P. Poupard,et al.  Identification and Quantification of a Phytotoxic Metabolite from Alternaria dauci , 2020, Molecules.

[16]  Shu-bin Niu,et al.  Alterchromanone A, one new chromanone derivative from the mangrove endophytic fungus Alternaria longipes , 2020, The Journal of Antibiotics.

[17]  Liman Zhou,et al.  Biphenyl metabolites from the patchouli endophytic fungus Alternaria sp. PfuH1. , 2020, Fitoterapia.

[18]  G. Del Favero,et al.  Alternaria alternata Toxins Synergistically Activate the Aryl Hydrocarbon Receptor Pathway In Vitro , 2020, Biomolecules.

[19]  W. Xu,et al.  Three new phomalone derivatives from a deep-sea-derived fungus Alternaria sp. MCCC 3A00467 , 2020, Natural product research.

[20]  Junjun Liu,et al.  Modified Fusicoccane-Type Diterpenoids from Alternaria brassicicola. , 2020, Journal of natural products.

[21]  T. Zhu,et al.  Cytotoxic Meroterpenoids from the Fungus Alternaria sp. JJY‐32 , 2020, Chemistry & biodiversity.

[22]  Junjun Liu,et al.  Fusicoccane-derived diterpenoids with bridgehead double-bond-containing tricyclo[9.2.1.03,7]tetradecane ring systems from Alternaria brassicicola. , 2020, Bioorganic chemistry.

[23]  A. Mándi,et al.  Alternarin A, a Drimane Meroterpenoid, Suppresses Neuronal Excitability from the Coral-Associated Fungi Alternaria sp. ZH-15. , 2020, Organic letters.

[24]  Ying Gao,et al.  Trichothecenes from an Endophytic Fungus Alternaria sp. sb23 , 2020, Planta Medica.

[25]  G. Mohamed,et al.  Naturally Occurring Isocoumarins Derivatives from Endophytic Fungi: Sources, Isolation, Structural Characterization, Biosynthesis, and Biological Activities , 2020, Molecules.

[26]  A. Yurchenko,et al.  Isolation and Bioactivity of Secondary Metabolites from Solid Culture of the Fungus, Alternaria sonchi , 2020, Biomolecules.

[27]  Jing-Wen Liu,et al.  Two new cephalochromin derivative from the Alternaria sp. ZG22 , 2019, Natural product research.

[28]  N. Kang,et al.  Secondary Metabolites of The Endophytic Fungus Alternaria alternata JS0515 Isolated from Vitex rotundifolia and Their Effects on Pyruvate Dehydrogenase Activity , 2019, Molecules.

[29]  N. Mandal,et al.  Inhibition of biofilm- and hyphal- development, two virulent features of Candida albicans by secondary metabolites of an endophytic fungus Alternaria tenuissima having broad spectrum antifungal potential. , 2019, Microbiological research.

[30]  A. Kaur,et al.  Assessment of alpha glucosidase inhibitors produced from endophytic fungus Alternaria destruens as antimicrobial and antibiofilm agents , 2019, Molecular Biology Reports.

[31]  Weiguang Sun,et al.  New cytotoxic tricycloalternarenes from fungus Alternaria brassicicola. , 2019, Bioorganic chemistry.

[32]  C. Shao,et al.  Alternatone A, an Unusual Perylenequinone-Related Compound from a Soft-Coral-Derived Strain of the Fungus Alternaria alternata. , 2019, Journal of natural products.

[33]  A. Zamilpa,et al.  α-Glucosidase inhibitory activity and in vivo antihyperglycemic effect of secondary metabolites from the leaf infusion of Ocimum campechianum mill. , 2019, Journal of ethnopharmacology.

[34]  Junjun Liu,et al.  Alterbrassinoids A-D: Fusicoccane-Derived Diterpenoid Dimers Featuring Different Carbon Skeletons from Alternaria brassicicola. , 2019, Organic letters.

[35]  M. Yar,et al.  Medicinal prospects of antioxidants: A review. , 2019, European journal of medicinal chemistry.

[36]  X. Liang,et al.  Novel anthraquinone derivatives as inhibitors of protein tyrosine phosphatases and indoleamine 2,3-dioxygenase 1 from the deep-sea derived fungusAlternaria tenuissimaDFFSCS013 , 2019, Organic Chemistry Frontiers.

[37]  P. Tu,et al.  Polyketides from Alternaria alternata MT-47, an endophytic fungus isolated from Huperzia serrata. , 2019, Fitoterapia.

[38]  Wenyuan Liu,et al.  Cytotoxic and neuroprotective activities of constituents from Alternaria alternate, a fungal endophyte of Psidium littorale. , 2019, Bioorganic chemistry.

[39]  H. Schwalbe,et al.  (±) Alternarlactones A and B, Two Antiparasitic Alternariol-like Dimers from the Fungus Alternaria alternata P1210 Isolated from the Halophyte Salicornia sp. , 2019, The Journal of organic chemistry.

[40]  J. Qin,et al.  Sesquiterpenoids and mycotoxin swainsonine from the locoweed endophytic fungus Alternaria oxytropis. , 2019, Phytochemistry.

[41]  M. Meena,et al.  Alternaria host-specific (HSTs) toxins: An overview of chemical characterization, target sites, regulation and their toxic effects , 2019, Toxicology reports.

[42]  Zonghui Ma,et al.  Chemical constituents from plant endophytic fungus Alternaria alternata , 2019, Natural product research.

[43]  Weiyan Zhang,et al.  Separation of five diketopiperazines from the marine fungus Alternaria alternate HK-25 by high-speed counter-current chromatography. , 2019, Journal of separation science.

[44]  Jae-Yong Kim,et al.  Chromones with lipoprotein oxidation inhibitory activity from an endophytic fungus Alternaria brassicae JS959 derived from Vitex rotundifolia , 2019, The Journal of Antibiotics.

[45]  A. Zaki,et al.  Production and enhancement of the acetylcholinesterase inhibitor, huperzine A, from an endophytic Alternaria brassicae AGF041 , 2019, Applied Microbiology and Biotechnology.

[46]  A. Zaki,et al.  Production and enhancement of the acetylcholinesterase inhibitor, huperzine A, from an endophytic Alternaria brassicae AGF041 , 2019, Applied Microbiology and Biotechnology.

[47]  Takeshi Yamada,et al.  Altercrasins A–E, Decalin Derivatives, from a Sea-Urchin-Derived Alternaria sp.: Isolation and Structural Analysis Including Stereochemistry , 2019, Marine drugs.

[48]  C. Liu,et al.  A new 2H-benzindazole compound from Alternaria alternata Shm-1, an endophytic fungus isolated from the fresh wild fruit of Phellinus igniarius , 2019, Journal of Natural Medicines.

[49]  C. Liu,et al.  Bialternacins A-F, Aromatic Polyketide Dimers from an Endophytic Alternaria sp. , 2019, Journal of natural products.

[50]  Jianguo Fang,et al.  (±)-Alternamgin, a Pair of Enantiomeric Polyketides, from the Endophytic Fungi Alternaria sp. MG1. , 2019, Organic letters.

[51]  Han-Dong Sun,et al.  (+)- and (-)-Alternarilactone A: Enantiomers with a Diepoxy-Cage-like Scaffold from an Endophytic Alternaria sp. , 2019, Journal of natural products.

[52]  Y. Chooi,et al.  Biosynthesis of bioactive natural products from Basidiomycota. , 2019, Organic & biomolecular chemistry.

[53]  N. Keller.  Fungal secondary metabolism: regulation, function and drug discovery , 2018, Nature Reviews Microbiology.

[54]  Junjun Liu,et al.  Alterbrassicicene A, a Highly Transformed Fusicoccane-Derived Diterpenoid with Potent PPAR-γ Agonistic Activity from Alternaria brassicicola. , 2018, Organic letters.

[55]  J. Williamson,et al.  Perylenequinones from an endophytic Alternaria sp. of Pinus ponderosa , 2018, Heliyon.

[56]  Yonghong Liu,et al.  Two New Altenusin/Thiazole Hybrids and a New Benzothiazole Derivative from the Marine Sponge-Derived Fungus Alternaria sp. SCSIOS02F49 , 2018, Molecules.

[57]  D. Wan,et al.  Cytotoxic Tricycloalternarene Compounds from Endophyte Alternaria sp. W-1 Associated with Laminaria japonica , 2018, Marine drugs.

[58]  Junjun Liu,et al.  Fusicoccane-Derived Diterpenoids from Alternaria brassicicola: Investigation of the Structure-Stability Relationship and Discovery of an IKKβ Inhibitor. , 2018, Organic letters.

[59]  Bin Yang,et al.  Perylenequione Derivatives with Anticancer Activities Isolated from the Marine Sponge-Derived Fungus, Alternaria sp. SCSIO41014 , 2018, Marine drugs.

[60]  Haifeng Wang,et al.  One pair of new cyclopentaisochromenone enantiomer from Alternaria sp. TNXY-P-1 and their cytotoxic activity , 2018, Journal of Asian natural products research.

[61]  Xiu-li Yin,et al.  Two new isomeric tricycloalternarenes from the marine alga‐epiphytic fungus Alternaria alternata k23‐3 , 2018, Magnetic resonance in chemistry : MRC.

[62]  Zhen-Zhen Shi,et al.  Two new tricycloalternarene esters from an alga-epiphytic isolate of Alternaria alternata , 2018, Natural product research.

[63]  Guangbo Ge,et al.  Carboxylesterase Inhibitors: An Update. , 2017, Current medicinal chemistry.

[64]  A. Miyanaga.  Structure and function of polyketide biosynthetic enzymes: various strategies for production of structurally diverse polyketides , 2017, Bioscience, biotechnology, and biochemistry.

[65]  Xiu-li Yin,et al.  Sesteralterin and Tricycloalterfurenes A-D: Terpenes with Rarely Occurring Frameworks from the Marine-Alga-Epiphytic Fungus Alternaria alternata k21-1. , 2017, Journal of natural products.

[66]  Hongxin Liu,et al.  Two New Metabolites from the Endophytic Fungus Alternaria sp. A744 Derived from Morinda officinalis , 2017, Molecules.

[67]  Hui Ding,et al.  Inhibitors of BRD4 Protein from a Marine-Derived Fungus Alternaria sp. NH-F6 , 2017, Marine drugs.

[68]  S. Nam,et al.  Potent Selective Inhibition of Monoamine Oxidase A by Alternariol Monomethyl Ether Isolated from Alternaria brassicae. , 2017, Journal of microbiology and biotechnology.

[69]  Jin-Ying Tian,et al.  Dibenzo-α-pyrones from the endophytic fungus Alternaria sp. Samif01: isolation, structure elucidation, and their antibacterial and antioxidant activities , 2017, Natural product research.

[70]  A. Patriarca,et al.  Alternaria Species and Their Associated Mycotoxins. , 2017, Methods in molecular biology.

[71]  G. Del Favero,et al.  Dual effectiveness of Alternaria but not Fusarium mycotoxins against human topoisomerase II and bacterial gyrase , 2016, Archives of Toxicology.

[72]  Qiao-yan Zhang,et al.  New cytotoxic compounds of endophytic fungus Alternaria sp. isolated from Broussonetia papyrifera (L.) Vent. , 2016, Fitoterapia.

[73]  W. Elkhateeb,et al.  Alternariol derivatives from Alternaria alternata, an endophytic fungus residing in red sea soft coral, inhibit HCV NS3/4A protease , 2015, Applied Biochemistry and Microbiology.

[74]  Jinhua Wang,et al.  Identification and Bioactivity of Compounds from the Mangrove Endophytic Fungus Alternaria sp. , 2015, Marine drugs.

[75]  Huan-Huan Bai,et al.  A new alternariol glucoside from fungus Alternaria alternate cib-137 , 2015, Natural product research.

[76]  李静,et al.  海百合Comanthina schlegeli共附生真菌Alternaria brassicae 93次级代谢产物研究 , 2015 .

[77]  Xiaobing Wang,et al.  Bioactive metabolites from the endophytic fungus Alternaria alternata. , 2014, Fitoterapia.

[78]  Yongcheng Lin,et al.  The Anthraquinone Derivatives from the Fungus Alternaria sp. XZSBG-1 from the Saline Lake in Bange, Tibet, China , 2014, Molecules.

[79]  D. Powell,et al.  Bioactive Sulfur-Containing Sulochrin Dimers and Other Metabolites from an Alternaria sp. Isolate from a Hawaiian Soil Sample , 2014, Journal of natural products.

[80]  Yongjun Lu,et al.  Alterporriol-Type Dimers from the Mangrove Endophytic Fungus, Alternaria sp. (SK11), and Their MptpB Inhibitions , 2014, Marine drugs.

[81]  Guo Ling-zh.  Secondary metabolites from the insect-derived endophytic Fungus Alternaria sp. , 2014 .

[82]  K. Matsubara,et al.  Antiangiogenetic effects of anthranoids from Alternaria sp., an endophytic fungus in a Thai medicinal plant Erythrina variegata. , 2013, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[83]  Ligang Zhou,et al.  Metabolites from Alternaria Fungi and Their Bioactivities , 2013, Molecules.

[84]  W. Bemmann.  Phytoeffective Alternaria-metabolite , 1986 .

[85]  P. W. Brian,et al.  Alternaric acid; a biologically active metabolic product of Alternaria solani (Ell. & Mart.) Jones & Grout; its production, isolation and antifungal properties. , 1951, Journal of general microbiology.