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Novel drugs with unique and targeted mode of action are very much need of the hour to treat and manage severe multidrug infections and other life-threatening complications. Though natural molecules have proved to be effective and environmentally safe, the relative paucity of discovery of new drugs has forced us to lean towards synthetic chemistry f...
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... mentioned earlier, endophytes have received much attention in the recent past due to their high metabolic versatility and several reviews have focused their attention of secondary metabolites produced by endophytes ( Aly et al., 2010;Guo et al., 2008;Schulz et al., 2002;Suryanarayanan et al., 2009;see Tan and Zou, 2001). While fungal endophytes have been vigorously screened for their potential to elicit host-derived phytochemicals, other reports clearly indicate that endophytic filamentous fungi also synthesize a diverse array of other secondary metabolites of significance (see Table 2). ...Citations
... Endophytes and host plants use these precursors in their respective SM biosynthesis processes. The biosynthetic pathway of SMs in EFs could be the result of their copying the host pathways [33,34]. Despite important studies on plant allelopathy, the particular contributions of rhizosphere-associated Bacillus strains to the allelopathic effects observed in C. equisetifolia are mainly unknown. ...
The coastal Casuarina equisetifolia is the most common tree species in Hainan’s coastal protection forests. Sequencing the genomes of its allelopathic endophytes can allow the protective effects of these bacteria to be effectively implemented in protected forests. The goal of this study was to sequence the whole genomes of the endophytes Bacillus amyloliquefaciens and Bacillus aryabhattai isolated from C. equisetifolia root tissues. The results showed that the genome sizes of B. amyloliquefaciens and B. aryabhattai were 3.854 Mb and 5.508 Mb, respectively. The two strains shared 2514 common gene families while having 1055 and 2406 distinct gene families, respectively. The two strains had 283 and 298 allelochemical synthesis-associated genes, respectively, 255 of which were shared by both strains and 28 and 43 of which were unique to each strain, respectively. The genes were putatively involved in 11 functional pathways, including secondary metabolite biosynthesis, terpene carbon skeleton biosynthesis, biosynthesis of ubiquinone and other terpene quinones, tropane/piperidine and piperidine alkaloids biosynthesis, and phenylpropanoid biosynthesis. NQO1 and entC are known to be involved in the biosynthesis of ubiquinone and other terpenoid quinones, and rfbC/rmlC, rfbA/rmlA/rffH, and rfbB/rmlB/rffG are involved in the biosynthesis of polyketide glycan units. Among the B. aryabhattai-specific allelochemical synthesis-related genes, STE24 is involved in terpene carbon skeleton production, atzF and gdhA in arginine biosynthesis, and TYR in isoquinoline alkaloid biosynthesis. B. amyloliquefaciens and B. aryabhattai share the genes aspB, yhdR, trpA, trpB, and GGPS, which are known to be involved in the synthesis of carotenoids, indole, momilactones, and other allelochemicals. Additionally, these bacteria are involved in allelochemical synthesis via routes such as polyketide sugar unit biosynthesis and isoquinoline alkaloid biosynthesis. This study sheds light on the genetic basis of allelopathy in Bacillus strains associated with C. equisetifolia, highlighting the possible use of these bacteria in sustainable agricultural strategies for weed management and crop protection.
... The antiSMASH employs a combination of computational algorithms and databases to analyze microbial genomes and predict the gene clusters associated with the secondary metabolites' biosynthesis [148]. The identification of the gene clusters involved in the biosynthesis of bioactive secondary metabolites in endophytic microorganisms gives possibilities for the manipulation and optimization of the compounds' production [149]. Therefore, in this section, we will explore the gene clusters of bioactive secondary metabolites in endophytic microorganisms and their importance in natural product discovery. ...
Infectious diseases are a significant challenge to global healthcare, especially in the face of increasing antibiotic resistance. This urgent issue requires the continuous exploration and development of new antimicrobial drugs. In this regard, the secondary metabolites derived from endophytic microorganisms stand out as promising sources for finding antimicrobials. Endophytic microorganisms, residing within the internal tissues of plants, have demonstrated the capacity to produce diverse bioactive compounds with substantial pharmacological potential. Therefore, numerous new antimicrobial compounds have been isolated from endophytes, particularly from endophytic fungi and actinomycetes. However, only a limited number of these compounds have been subjected to comprehensive studies regarding their mechanisms of action against bacterial cells. Furthermore, the investigation of their effects on antibiotic-resistant bacteria and the identification of biosynthetic gene clusters responsible for synthesizing these secondary metabolites have been conducted for only a subset of these promising compounds. Through a comprehensive analysis of current research findings, this review describes the mechanisms of action of antimicrobial drugs and secondary metabolites isolated from endophytes, antibacterial activities of the natural compounds derived from endophytes against antibiotic-resistant bacteria, and biosynthetic gene clusters of endophytic fungi responsible for the synthesis of bioactive secondary metabolites.
... The biosynthetic pathway of Taxol in fungi started with cyclization of geranylgeranyl diphosphate to taxa-4(5), 11(12)-diene by the action of taxadiene synthase, then hydroxylation of taxadiene nucleus by the cytochrome P450-monooxygenases, as reviewed in details by our previous studies [21]. However, the anticipation of fungi to be a commercial approach for Taxol production has been confronted by the attenuation of Taxol productivity by fungi with the storage and multiple subculturing [16,[21][22][23][24]. The machinery of Taxol biosynthesis in fungi is usually encoded by gene cluster located on different domains on the fungal genome, and the expression of these cluster become cryptic under standard lab conditions, due to the lack or dilution of the transcriptional signals to synchronize the expression of these genes [18,[24][25][26][27][28]. ...
... However, the anticipation of fungi to be a commercial approach for Taxol production has been confronted by the attenuation of Taxol productivity by fungi with the storage and multiple subculturing [16,[21][22][23][24]. The machinery of Taxol biosynthesis in fungi is usually encoded by gene cluster located on different domains on the fungal genome, and the expression of these cluster become cryptic under standard lab conditions, due to the lack or dilution of the transcriptional signals to synchronize the expression of these genes [18,[24][25][26][27][28]. Thus, screening for a metabolically stable Taxol producing fungal isolate from different medicinal plants is the objective. ...
Production and bioprocessing of Taxol
from Aspergillus niger, an endophyte
of Encephalartos whitelockii, with a plausible
biosynthetic stability: antiproliferative activity
and cell cycle analysis
... The biosynthetic pathway of Taxol in fungi started with cyclization of geranylgeranyl diphosphate to taxa-4(5), 11(12)-diene by the action of taxadiene synthase, then hydroxylation of taxadiene nucleus by the cytochrome P450-monooxygenases, as reviewed in details by our previous studies [21]. However, the anticipation of fungi to be a commercial approach for Taxol production has been confronted by the attenuation of Taxol productivity by fungi with the storage and multiple subculturing [16,[21][22][23][24]. The machinery of Taxol biosynthesis in fungi is usually encoded by gene cluster located on different domains on the fungal genome, and the expression of these cluster become cryptic under standard lab conditions, due to the lack or dilution of the transcriptional signals to synchronize the expression of these genes [18,[24][25][26][27][28]. ...
... However, the anticipation of fungi to be a commercial approach for Taxol production has been confronted by the attenuation of Taxol productivity by fungi with the storage and multiple subculturing [16,[21][22][23][24]. The machinery of Taxol biosynthesis in fungi is usually encoded by gene cluster located on different domains on the fungal genome, and the expression of these cluster become cryptic under standard lab conditions, due to the lack or dilution of the transcriptional signals to synchronize the expression of these genes [18,[24][25][26][27][28]. Thus, screening for a metabolically stable Taxol producing fungal isolate from different medicinal plants is the objective. ...
The biosynthetic potency of Taxol by fungi raises their prospective to be a platform for commercial production of Taxol, nevertheless, the attenuation of its productivity with the fungal storage, is the challenge. Thus, screening for a novel fungal isolate inhabiting ethnopharmacological plants, with a plausible metabolic stability for Taxol production could be one of the most affordable approaches. Aspergillus niger OR414905.1, an endophyte of Encephalartos whitelockii, had the highest Taxol productivity (173.9 μg/L). The chemical identity of the purified Taxol was confirmed by HPLC, FTIR, and LC–MS/MS analyses, exhibiting the same molecular mass (854.5 m/z) and molecular fragmentation pattern of the authentic Taxol. The purified Taxol exhibited a potent antiproliferative activity against HepG-2, MCF-7 and Caco-2, with IC50 values 0.011, 0.016, and 0.067 μM, respectively, in addition to a significant activity against A. flavus, as a model of human fungal pathogen. The purified Taxol displayed a significant effect against the cellular migration of HepG-2 and MCF-7 cells, by ~ 52–59% after 72 h, compared to the control, confirming its interference with the cellular matrix formation. Furthermore, the purified Taxol exhibited a significant ability to prompt apoptosis in MCF-7 cells, by about 11-fold compared to control cells, suppressing their division at G2/M phase. Taxol productivity by A. niger has been optimized by the response surface methodology with Plackett–Burman Design and Central Composite Design, resulting in a remarkable ~ 1.6-fold increase (279.8 μg/L), over the control. The biological half-life time of Taxol productivity by A. niger was ~ 6 months of preservation at 4 ℃, however, the Taxol yield by A. niger was partially restored in response to ethyl acetate extracts of E. whitelockii, ensuring the presence of plant-derived signals that triggers the cryptic Taxol encoding genes.
... Another theory focuses on extrachromosomal DNA (ecDNA), such as organelles and plasmids, whose loss may be the genetic cause for sudden attenuations in both endophytic fungi and bacteria [179,180]. Extrachromosomal DNA elements are the primary agents of horizontal gene transfer; consequently, a host plant is able to transfer some of its genes onto its microbial locators [179,181]. Soujanya et al. (2017) reported CPT production by the endophytic bacteria from Pyrenacanha volubilis; however, this gradually decreased until the sixth subculture, where CPT was not detected. ...
For thousands of years, plants have been used for their medicinal properties. The industrial production of plant-beneficial compounds is facing many drawbacks, such as seasonal dependence and troublesome extraction and purification processes, which have led to many species being on the edge of extinction. As the demand for compounds applicable to, e.g., cancer treatment, is still growing, there is a need to develop sustainable production processes. The industrial potential of the endophytic microorganisms residing within plant tissues is undeniable, as they are often able to produce, in vitro, similar to or even the same compounds as their hosts. The peculiar conditions of the endophytic lifestyle raise questions about the molecular background of the biosynthesis of these bioactive compounds in planta, and the actual producer, whether it is the plant itself or its residents. Extending this knowledge is crucial to overcoming the current limitations in the implementation of endophytes for larger-scale production. In this review, we focus on the possible routes of the synthesis of host-specific compounds in planta by their endophytes.
... Various signaling proteins play a role in metabolite regulation by transmitting environmental signals such as PacC involved in pH signaling, CreA protein in carbon signaling and AreA in nitrogen signaling which are zincfinger proteins of Cys2His2 type (Deepika et al. 2016). Thus, environmental conditions influence the production of metabolites which further have an impact on resistance against pest. ...
... Thus, endophytes have both negative and positive impact on tissue culture. Negative impact of EF in tissue culture is being a contaminant or when it is unwanted, and repeated sub-culturing of EF leads to lose their ability to produce secondary metabolites (Deepika et al. 2016). Positive impact of EF in tissue culture includes bioactive molecule accumulation and protection of the callus and plant parts from external environmental conditions. ...
... The euphorbiaceae family is known for many biodiesel producing plants and the same property has been observed in the endophytes of plants. The reason may be horizontal gene transfer between fungus and host plant another hypothesis is that the microorganisms might sense any stress in plant by stress-induced molecules from plants and homologous gene clusters present in plants and microorganisms may get cross-activated (Deepika et al. 2016). ...
Main conclusion
EF have been explored for its beneficial impact on environment and for its commercial applications. It has proved its worth in these sectors and showed an impact on biological properties of plants by producing various bioactive molecules and enzymes.
Abstract
Endophytes are plant mutualists that live asymptomatically within plant tissues and exist in almost every plant species. Endophytic fungi benefit from the host plant nutrition, and the host plant gains improved competitive abilities and tolerance against pathogens, herbivores, and various abiotic stresses. Endophytic fungi are one of the most inventive classes which produce secondary metabolites and play a crucial role in human health and other biotic aspects. This review is focused on systematic study on the biodiversity of endophytic fungi in plants, and their role in enhancing various properties of plants such as antimicrobial, antimycobacterial, antioxidant, cytotoxic, anticancer, and biological activity of secondary metabolites produced by various fungal endophytes in host plants reported from 1994 to 2021. This review emphasizes the endophytic fungal population shaped by host genotype, environment, and endophytic fungi genotype affecting host plant. The impact of endophytic fungi has been discussed in detail which influences the commercial properties of plants. Endophytes also have an influence on plant productivity by increasing parameters such as nutrient recycling and phytostimulation. Studies focusing on mechanisms that regulate attenuation of secondary metabolite production in EF would provide much needed impetus on ensuring continued production of bioactive molecules from a indubitable source. If this knowledge is further extensively explored regarding fungal endophytes in plants for production of potential phytochemicals, then it will help in exploring a keen area of interest for pharmacognosy.
... Importantly, bioactive secondary metabolites from microorganisms are considered advantageous due to less destruction of resources, sustainable use, large scale industrial productions and quality control (Liang et al., 2012). They are endowed with a collection of enzymes that aid in the biosynthesis of structurally diverse and complex molecules that are often difficult to mimic (Deepika et al, 2016). ...
... The instability of the expression of genes involved in the biosynthesis of desired metabolite(s) is a major limitation in the production of bioactive SMs in current fermentation practices using fungal endophytes (Pandey et al., 2014). Endophytic fungi, on the other hand, exhibit a typical tendency to lose their ability to produce secondary metabolites after repeated sub-culturing in axenic medium (Deepika et al., 2016). As a result of these, there is a need to develop techniques that can be used to activate cryptic biosynthetic pathways in order to increase SMs biosynthesis in fungal endophytes. ...
In the science of drug discovery, ultraviolet (UV) irradiation has been applied to induce mutagenesis in fungi to provide possibilities for the stimulation or enhancement of fungal biosynthetic capabilities. This study was carried out to evaluate the effect of UV radiation on the biosynthesis of antibacterial secondary metabolites in an endophytic Lasiodiplodia theobromae. Using standard methods, the fungus was isolated from healthy leaves of Cola acuminata and identified based on PCR amplification and genomic sequencing of the internal transcribed spacer (ITS) region. Cultures of L. theobromae were exposed to UV radiation at different time intervals of 1, 2 and 5 min. The fungus was subjected to solid-state fermentation in rice medium before and after UV treatments. The fungal secondary metabolites were extracted and tested for antibacterial activity using the agar diffusion method. Compounds present in the obtained extracts were identified by HPLC and GC-MS analysis. At a concentration of 1 mg/ml, the extract of the wild type L. theobromae (untreated) was observed to only inhibit Staphylococcus aureus, with an IZD of 12 mm. However, the extract of UV-treated L. theobromae (2 min) inhibited S. aureus, Escherichia coli and Pseudomonas aeruginosa with an IZD of 10 and 4 mm respectively. A wide array of compounds in the phenolics, fatty acids, alkaloids and alkanes classes were identified in the UV-treated and untreated fungal extracts. Overall, UV treatments of L. theobromae stimulated the production of seventeen (17) new compounds that were not detected in the untreated strain. The study confirms UV irradiation as an effective method for stimulating microbial biosynthesis of new bioactive compounds, indicating a promising and potentially abundant source of new drug compounds from microorganism
... Importantly, bioactive secondary metabolites from microorganisms are considered advantageous due to less destruction of resources, sustainable use, large scale industrial productions and quality control (Liang et al., 2012). They are endowed with a collection of enzymes that aid in the biosynthesis of structurally diverse and complex molecules that are often difficult to mimic (Deepika et al, 2016). ...
... The instability of the expression of genes involved in the biosynthesis of desired metabolite(s) is a major limitation in the production of bioactive SMs in current fermentation practices using fungal endophytes (Pandey et al., 2014). Endophytic fungi, on the other hand, exhibit a typical tendency to lose their ability to produce secondary metabolites after repeated sub-culturing in axenic medium (Deepika et al., 2016). As a result of these, there is a need to develop techniques that can be used to activate cryptic biosynthetic pathways in order to increase SMs biosynthesis in fungal endophytes. ...
In the science of drug discovery, ultraviolet (UV) irradiation has been applied to induce mutagenesis in fungi to provide possibilities for the stimulation or enhancement of fungal biosynthetic capabilities. This study was carried out to evaluate the effect of UV radiation on the biosynthesis of antibacterial secondary metabolites in an endophytic Lasiodiplodia theobromae. Using standard methods, the fungus was isolated from healthy leaves of Cola acuminata and identified based on PCR amplification and genomic sequencing of the internal transcribed spacer (ITS) region. Cultures of L. theobromae were exposed to UV radiation at different time intervals of 1, 2 and 5 min. The fungus was subjected to solid-state fermentation in rice medium before and after UV treatments. The fungal secondary metabolites were extracted and tested for antibacterial activity using the agar diffusion method. Compounds present in the obtained extracts were identified by HPLC and GC-MS analysis. At a concentration of 1 mg/ml, the extract of the wild type L. theobromae (untreated) was observed to only inhibit Staphylococcus aureus, with an IZD of 12 mm. However, the extract of UV-treated L. theobromae (2 min) inhibited S. aureus, Escherichia coli and Pseudomonas aeruginosa with an IZD of 10 and 4 mm respectively. A wide array of compounds in the phenolics, fatty acids, alkaloids and alkanes classes were identified in the UV-treated and untreated fungal extracts. Overall, UV treatments of L. theobromae stimulated the production of seventeen (17) new compounds that were not detected in the untreated strain. The study confirms UV irradiation as an effective method for stimulating microbial biosynthesis of new bioactive compounds, indicating a promising and potentially abundant source of new drug compounds from microorganisms.
... The SMs are represented mainly by polyketides, nonribosomal peptides (NRPs), ribosomal peptides, terpenes, shikimate-derived, and compounds that emerged from hybrid pathways [13,14,[64][65][66][67][68]. The classification of these molecules is related to the primary metabolites from which they are derived and built through building blocks, forming molecules that are more complex. ...
... The cellular regulatory elements and mechanisms involved in the biosynthetic pathways of SMs by microorganisms were previously very well discussed [13,14,[66][67][68]. Particularly in fungi, the SMs are chemical classes classified according to their starter substrates (acyl-CoA, amino acids, nucleotides, carbohydrates, etc.), which are commonly incorporated in the final structure by specific enzymes, such as polyketide synthases (PKSs), nonribosomal peptide synthetases (NRPSs), dimethylallyl tryptophan synthetases (DMAT), geranylgeranyl diphosphate synthetases (GGPS), prenyltransferases, and terpene cyclases (TC) [13,14,[65][66][67][68]. ...
... The cellular regulatory elements and mechanisms involved in the biosynthetic pathways of SMs by microorganisms were previously very well discussed [13,14,[66][67][68]. Particularly in fungi, the SMs are chemical classes classified according to their starter substrates (acyl-CoA, amino acids, nucleotides, carbohydrates, etc.), which are commonly incorporated in the final structure by specific enzymes, such as polyketide synthases (PKSs), nonribosomal peptide synthetases (NRPSs), dimethylallyl tryptophan synthetases (DMAT), geranylgeranyl diphosphate synthetases (GGPS), prenyltransferases, and terpene cyclases (TC) [13,14,[65][66][67][68]. ...
Microorganisms are known as important sources of natural compounds that have been studied and applied for different purposes in distinct areas. Specifically, in the pharmaceutical area, fungi have been explored mainly as sources of antibiotics, antiviral, anti-inflammatory, enzyme inhibitors, hypercholesteremic, antineoplastic/antitumor, immunomodulators, and immunosuppressants agents. However, historically, the high demand for new antimicrobial and antitumor agents has not been sufficiently attended by the drug discovery process, highlighting the relevance of intensifying studies to reach sustainable employment of the huge world biodiversity, including the microorganisms. Therefore, this review describes the main approaches and tools applied in the search for bioactive secondary metabolites, as well as presents several examples of compounds produced by different fungi species with proven pharmacological effects and additional examples of fungal cytotoxic and antimicrobial molecules. The review does not cover all fungal secondary metabolites already described; however, it presents some reports that can be useful at any phase of the drug discovery process, mainly for pharmaceutical applications.
... The TFs are involved in controlling various aspects of fungal development, stress tolerance, and the biosynthesis of virulence factors such as effectors and secondary metabolites. There are a significant number of Zn(II) 2 Cys6 TF encoding genes, whose activation or functional products have not been resolved (Deepika et al., 2016;Keller, 2019;Romsdahl and Wang, 2019;Graham-Taylor et al., 2020). Here, we reported a new Zn(II) 2 Cys6 TF, BcSpd1, that played a key role in B. cinerea. ...
Botrytis cinerea is a necrotrophic microbe that causes gray mold disease in a broad range of hosts. In the present study, we conducted molecular microbiology and transcriptomic analyses of the host–B. cinerea interaction to investigate the plant defense response and fungal pathogenicity. Upon B. cinerea infection, plant defense responses changed from activation to repression; thus, the expression of many defense genes decreased in Arabidopsis thaliana. B. cinerea Zn(II)2Cys6 transcription factor BcSpd1 was involved in the suppression of plant defense as ΔBcSpd1 altered wild-type B05.10 virulence by recovering part of the defense responses at the early infection stage. BcSpd1 affected genes involved in the fungal sclerotium development, infection cushion formation, biosynthesis of melanin, and change in environmental pH values, which were reported to influence fungal virulence. Specifically, BcSpd1 bound to the promoter of the gene encoding quercetin dioxygenase (BcQdo) and positively affected the gene expression, which was involved in catalyzing antifungal flavonoid degradation. This study indicates BcSpd1 plays a key role in the necrotrophic microbe B. cinerea virulence toward plants by regulating pathogenicity-related compounds and thereby suppressing early plant defense.
