Kaurene, isolated from members of the Asteraceae family, has good anti-cluster induction activity against C. albicans Dal Piaz et al. The upregulated expression of the terpene synthase gene OsTPS19 in rice can promote the production of limonene and enhance its defense against Aspergillus oryzae infection Chen et al.

Meanwhile, limonene can induce C. In addition, limonene showed significant antifungal activity against A. fumigatus , Cryptococcus neoformans , T. rubrum , and T. mentagrophytes Pinto et al. Citronellal can inhibit the growth of C.

albicans by destroying the cell membrane integrity, inhibiting biofilm formation, and blocking the fungal cell cycle Trindade et al. What is more, citronellal can downregulate expression of the erg3 gene to inhibit the transformation of lanosterol into ergosterol, inhibiting the growth of Penicillium OuYang et al.

Moreover, the combination of carvone and AmB greatly increased the inhibition of the growth rate of C. albicans O'Brien et al. In addition, geraniol, widely distributed in geranium, rose, bee-sweet mint, and other plant species, could inhibit C.

albicans from forming pseudomycelia and chlamydia spores and increased fungal cell membrane permeability, leading to intracellular potassium outflow Leite et al. At the same time, it was also found that geraniol has a marked antifungal effect on A. niger Kamatou et al. Thymol, a monoterpenoid phenolic derivative isolated from Syringa , among other species, had a significant antifungal effect on C.

albicans and C. tropicalis ; moreover, the minimum inhibitory concentration MIC value of nystatin was decreased by In the mouse vaginal Candida model, limonene treatment significantly reduced the fungal load Munoz et al. In recent years, further investigations have found that terpenoids regulate the immune function of the human body and improve various symptoms caused by inflammation.

Soybean saponins played an anti-inflammatory role by inhibiting the degradation of an inhibitor of NF-κBα IκBα and activating NF-κB to downregulate the production of cyclooxygenase-2 COX-2 , nitric oxide synthase iNOS , human macrophage chemoattractant protein-1 MCP-1 , and TNF-α in lipopolysaccharide LPS -stimulated RAW Meanwhile, quinoa saponins, with a dose-dependent action, could downregulate the secretion of TNF-α, nitric oxide NO , and IL-6 in LPS-activated RAW In addition, laurene can inhibit the activation of NF-κB, c-Jun N-terminal kinase JNK , and p38 in human chondrocytes induced by IL-1β.

β-patchoulene significantly altered sepsis-induced neuroinflammation and microglia activation and improved the peripheral immune function Tian et al.

In a mouse model of acute inflammation, β-patchoulene alleviated edema and inflammatory cell infiltration. β-patchoulene, in a dose-dependent manner, inhibited the secretion of IL-6, TNF-α, and IL-1β in a mouse model of inflammation and could significantly downregulate the expression of genes iNOS and COX-2 Zhang et al.

Furthermore, ganoderic acid, a triterpenoid compound extracted from the Chinese medicinal mushroom Ganoderma lucidum , was found to significantly inhibit phorbol ester-induced inflammation in mice Akihisa et al.

Therefore, terpenoids have an effect on the growth, inhibition, and killing of common human-pathogenic fungi and phytopathogenic fungi. At the same time, some terpenoids can also help the host to regulate and balance the inflammatory state of the body in the face of fungal infection by regulating the secretion of related cytokine.

Phenolic compounds are one of the most common classes of plant secondary metabolites; more than phenolic compounds with known structures are found in plants. Most phenolic compounds in plants are synthesized by the shikimic acid the major pathway and malonic acid pathways.

These compounds are formed by an aromatic ring or rings combined with one or multiple hydroxyl groups. Phenolics are mainly composed of polymeric or monomeric structures, which can exist in the form of glycosides, aglycones, substrates, or free-binding compounds Alara et al.

Phenolic compounds include flavonoids, phenolic acids, and polyphenols and tannins and can be found in fruits, vegetables, legumes, and tea. In addition, biological functions of phenolic compounds include antioxidant, antibacterial, anti-inflammatory, analgesic, antipyretic, and anti-tumor, among others Alara et al.

In recent years, more and more natural plant phenolic compounds have been recognized, and they have become an important research target for the development of novel antifungal agents Chtioui et al.

Flavonoids are hydroxylated phenolic molecules with a C 6 -C 3 -C 6 carbon skeleton structure, connecting two aromatic rings with a heterocyclic ring containing three carbon atoms. Since the first discovery of flavonoids in orange peel in , more than flavonoids have been identified in plants. Therefore, flavonoids represent one of the most important classes of the phenolic family and account for one-half of the total number of phenolic compounds.

For the human body, flavonoids in fruits and vegetables are directly related to the health status of the human diet, contributing to anticancer activity and prevention of cardiovascular diseases Middleton ; Tungmunnithum et al.

In addition, investigations have found that natural flavonoids have the ability to act directly as antifungal molecules and to interact synergistically with other antifungals Jin It has also been reported that some flavonoids can significantly reduce the spore germination of plant-pathogenic fungi, such as Botryosphaeria Ma et al.

Therefore, flavonoids are expected to become one of the important research targets from which to develop antifungal drugs. It has been confirmed that certain flavonoid compounds have antifungal activities against human pathogens such as Aspergillus Wang et al.

Alves et al. albicans Valsaraj et al. The reason why the propolis has an inhibitory effect on Aspergillus niger and C. albicans is that it contains a high concentration of flavonoids Vică et al.

In addition, curcumin from Curcuma longa L. has a fungistatic effect on A. flavus Temba et al. Additionally, the flavonoid baicalin, the main bioactive component of the traditional Chinese medicinal plant Scutellaria baicalensis , exerts a concentration-dependent antifungal effect by inhibition of C.

albicans biofilm formation and increasing the apoptosis rate of this human pathogen Cao et al. albicans apoptosis rate Cao et al. In addition to C. albicans , baicalin also has antifungal effects on A.

fumigatus , T. rubens , and T. trichophyton Da et al. Moreover, quercetin, extracted from Morus alba L.

fumigatus , with the fungal load in the corneal tissue of mice treated with quercetin being significantly lower than in control mice Yin et al. In addition to flavonoids, the polyphenol chlorogenic acid, widely found in apple, coffee, potato, and tomato, has a synergistic antifungal effect in combination with FLC on C.

albicans and Malassezia spp. Rhimi et al. In addition, chlorogenic acid was found to have antifungal effects against phytopathogenic fungi such as Fusarium spp. and Verticillium dahliae through a reactive oxygen species ROS -dependent mode of action and alteration of fungal cell membrane permeability Kai et al.

In addition, gallic acid, another class phenolic acid of phenolic compound, also had antifungal effects on C. albicans Teodoro et al. In addition to effects on A. fumigatus and A.

niger , resveratrol another polyphenol not only inhibits biofilm formation of C. albicans , but also has an inhibitory effect on the growth of superficial skin fungi, especially Epidermophyton floccosum , Microsporum gypseum , T.

mentagrophytes , T. tonsurans , and T. rubrum Jediyi et al. Pterostilbene a demethylated derivative of resveratrol , extracted from grape leaves, is one of the more active antifungal compounds against C.

albicans , downregulating the expression of genes involved in ergosterol biosynthesis Li et al. In addition, in the biofilm model of rat central venous catheter, defects in C. Interestingly, the antifungal effect of pterostilbene against C. albicans exceeded that of resveratrol. Recent investigations found that the licochalcone A in the ethanol extract from the licorice roots of Glycyrrhiza species significantly inhibited the formation of the C.

albicans biofilm, and the fungal load in tongues of mice treated with these isoprene acylated ketones was significantly lower in the oral Candida mouse model than that in the control mice Seleem et al.

Many phenolic compounds have anti-inflammatory and antioxidant effects Dominguez-Avila et al. For example, gingerol extracted from ginger rhizomes has high antioxidant activity.

The potential antioxidant mechanism of gingerol in human intestinal epithelial cells prevents the degradation of Keap1-Nrf2 protease, promotes the translocation of Nrf2 into the nucleus, increases the expression of Nrf2 target genes, and increases the level of the antioxidant reduced glutathione, decreasing the concentration of ROS.

Moreover, gingerol also reduces the production of NO and prostaglandin E2 PGE2 in RAW Quercetin acts on immune cells and then targets intracellular signaling kinases, phosphatases, and membrane proteins to regulate cell-specific functions.

Therefore, there is a hypothesis that quercetin is an immunomodulatory molecule. In LPS-activated RAW Kaempferol, a flavonol, which is a type of flavonoid, also exerts anti-inflammatory effects by inhibiting the activity of hyaluronidase and reducing the level of ROS produced during cell stimulation Yang et al.

Chlorogenic acid, gallic acid, and kaempferol showed anti-inflammatory activities by inhibiting the expression of iNOS , secretion of pro-inflammatory factors, and production of ROS in LPS-induced RAW Ferulic acid, a phenolic acid compound, has been shown to play an anti-inflammatory role in bovine endometrial epithelial cells by inhibiting IκB degradation, the phosphorylation of NF-κB p65 and mitogen-activated protein kinase, and reducing the production of the pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α Yin et al.

Quercetin and resveratrol exert anti-inflammatory effects by downregulating expression at the mRNA and protein levels of NO, iNOS, TNF-α, IL-1β, IL-6, and the granulocyte—macrophage colony-stimulating factor GM-CSF Endale et al.

Moreover, quercetin reduced IL-8 production in LPS-activated lung A cells Geraets et al. It was also reported that quercetin and resveratrol could significantly reduce TNF-α production in LPS-activated microglia, and resveratrol also could inhibit IL-1 production Bureau et al.

After feeding quercetin to healthy broiler chickens for 6 weeks, the concentration of serum immunoglobulin, IL-4, as well as the spleen index, thymus index, and bursa of Fabricius index, were all increased. These data indicated that quercetin can enhance the immune ability of animals by stimulating the development of immune organs and the subsequent amplification of humoral immunity Yang et al.

A small number of phenolic compounds such as quercetin and resveratrol with antifungal effects also have immunomodulatory effects on the body, which is one of the promising new drug research and development targets. Nitrogenous secondary compounds are another type of secondary metabolites in plants, most of which are synthesized from amino acids.

Their metabolism is complicated and can be affected by plant hormones and environmental stress Cho et al. Nitrogen-containing secondary metabolites include alkaloids, cyanogenic glycosides CNGs , and non-protein amino acids. CNGs, glycosides with α-hydroxynitrile, are composed of an aglycone with a sugar group attached Bolarinwa et al.

CNGs are potentially highly toxic substance, releasing hydrogen cyanide when hydrolyzed, although the compounds themselves are not toxic, and may lead to acute cyanide poisoning Cressey et al. Another class of plant nitrogenous compounds is non-protein amino acids, which are important stores of nitrogen in plants.

In addition to their antibacterial, antifungal, and anticancer effects, non-protein amino acids primarily help plants to resist harmful insects Huang et al. They are compounds that contain at least one nitrogen atom in a naturally occurring heterocyclic ring.

According to the chemical structure classification, alkaloids can be divided into pyridine, isoquinoline, indole, scopolamine, and organic amine alkaloids, among others. Alkaloids have a range of biological activities and are used in treatment of bacterial infections, cancer, dementia, and pain and are an important source of many drugs Adamski et al.

Here, the antifungal effects of alkaloids will be discussed. Alkaloids extracted from sea buckthorn Hippophae rhamnoides , including acridone, fluoroquinolone, and 4-quinolone, play an inhibitory role against fungi by downregulating the expression of the ICL1 gene in C.

albicans Kamal et al. Magnoflorine, present in Acorus calamus , Tinospora cordifolia , and Celastrus paniculatus , exerts antifungal effects by inhibiting α-glucosidase activity and reducing biofilm formation in C.

albicans Kim et al. Meanwhile, magnoflorine can also damage the T. rubrum cell membrane, increasing the leakage of nucleic acids from fungal cells, reducing the activities of squalene epoxidase and α-lanosterol demethylase, and reducing the concentration of ergosterol in mycelia Luo et al.

In addition, graveoline, from rue Ruta graveolens , showed significant antifungal activity against C. albicans , Fusarium oxysporum , and T. rubrum Cantrell et al. Pteleine, one of the furanoquinoline alkaloids, exhibits antifungal activity against C. albicans Shang et al. Recent investigations also found that 8-acetylnorchylerythrine and 8-methoxydictamnine, from Zanthoxylum Toddalia asiatica , exhibit antifungal activity against C.

albicans , Candida glabrata , and Candida tropicalis Hu et al. The half-maximal inhibitory concentration IC 50 values of 2,3-dihydro-1H-indolizinium chloride, an indoleazine alkaloid extracted from the fern Dryopteris enneaphylla , against A. fumigatus and C. neoformans were 0.

Berberine, isolated from Coptis chinensis and Phellodendron chinense , exerted an antifungal effect on C. albicans by upregulating the expression of core genes sln1 , ssk2 , hog1 , and pbs2 and inducing ROS accumulation and inhibiting the expression of the chitin synthase gene chs3 and the β- 1,3 -glucan synthase gene gsc1 to damage the integrity of the cytoplasm, inhibit the formation of germ tubes and hyphae, and destroy the integrity of cell wall Huang et al.

Berberine also exerted synergistic antifungal spread ability in vivo when combined with AmB or FLC; when berberine was combined with AmB, the survival time of mice with disseminated infection of pathogenic C. albicans was increased from 14 to 36 d Huang et al. To regulate the immune response, steroidal alkaloids, from the bulbs of Fritillaria spp.

of the Liliaceae , blocked LPS-induced phosphorylation and degradation of both IκBα and JNK and significantly inhibited the production of NO, IL-6, and TNF-α in RAW In addition, oral administration of sinomenine could reduce the activities of iNOS and COX-2 in rats Zhu et al.

Furthermore, aconitine can improve LPS-induced acute lung injury in rats by inhibiting the activation of NF-κB and reducing the concentrations of TNF-α, IL-6, and IL-1β Wang et al.

Moreover, berberine and matrine from Sophora sp. are more effective against inflammation, with berberine reducing the concentration of COX-2 and inhibiting the synthesis of PGE2 to achieve the anti-swelling effect in the formalin-induced foot swelling mice model Yao et al.

Berberine also had an inhibitory effect on the secretion of inflammatory factors, including TNF-α, IL-8, IL-6, and MCP-1, in dinitrofluorobenzene-induced delayed-type hypersensitivity rat model. Recent studies also found that matrine, isolated from the roots of Sophora flavescens , has a strong negative regulatory effect on the secretion of TNF-α, IL-8, and IL-1α in THP-1 cells Zhou et al.

It also exerted anti-inflammatory effects by downregulating the expression of the genes encoding lipopolysaccharide recognition receptor, lipopolysaccharide-binding protein, CD14 and TLR4, and the transcription of the nuclear factors c-Jun and c-fos in the mouse model of foot swelling Li et al.

In addition, matrine inhibited the NF-κB signaling pathway in mouse airway epithelial cells, reduced the expression of suppressors of cytokine signaling 3, and reduced the production of ROS and inflammatory factors in alveolar macrophages to inhibit airway inflammation in a mouse model of asthma Li et al.

Therefore, alkaloids mainly improve inflammation by inhibiting related inflammatory factors and signaling pathways and then play a role in immune regulation in the body. In addition to terpenoids, phenolics, and nitrogen-containing secondary compounds, plant-derived essential oils, also known as volatile oils, have attracted much attention for their antifungal activities.

Essential oils are a mixture of secondary metabolites. Most are volatile aromatic oil-like liquids, containing aliphatic compounds, aromatic compounds, sulfur and nitrogen compounds, and terpenes and their oxygen derivatives.

Since , more than articles have reported on the antifungal properties of essential oils Kalemba and Kunicka Essential oils have been listed as the most widely used special plant metabolites due to their anti-infective properties Plant et al.

Investigations have shown that essential oils have significant antifungal effects, not only on deep fungal infections caused by Aspergillus and Candida , but also on superficial fungal infections caused by Microsporum canis , M.

gypseum , T. mentagrophytes , and even on phytopathogenic fungi in crops Bakkali et al. The antifungal targets of essential oils mainly involve inhibition of fungal cell growth and mycotoxin synthesis, for example, by disruption of cell membrane permeability and intracellular electron transport chains, resulting in intracellular metabolic disorders Mirza Alizadeh et al.

Investigations have found that rosemary Rosmarinus officinalis essential oil not only targets mycelial ergosterol synthesis to inhibit toxin biosynthesis in A.

flavus , but also inhibits mycelium growth to play an antifungal effect on the phytopathogen F. oxysporum da Silva Bomfim et al. Furthermore, Rhododendron tomentosum essential oils not only have an inhibitory effect on Candida parapsilosis , but also play an antifungal role in affecting the permeability of cell membranes in the yeast, Saccharomyces cerevisiae Judzentiene et al.

The concentrations of thyme essential oil and ginger essential oil were In addition to extensive antibacterial activity, Bupleurum rigidum essential oil can also play an antifungal role by changing the ultrastructure of C.

albicans , C. neoformans , and T. rubrum Zuzarte et al. Melaleuca alternifolia essential oil, which is mainly pinenealcohol, showed antifungal activity in vitro against A.

niger and both azole-sensitive and azole-resistant C. albicans Hammer et al. albicans infection model, this essential oil also had a great impact on eliminating C. albicans infection and enhancing the anti-infection ability Mondello et al.

Oregano oil at a concentration of 0. albicans in vitro. In addition, it also inhibited spore germination and mycelium growth in a concentration-dependent manner Manohar et al. Sodium houttuyfonate SH , a volatile oil from Houttuynia cordata , exerted an antifungal effect on C.

albicans by affecting gene expression in the Ras1-cAMP-Efg1 pathway and decreasing biofilm formation and the production of cAMP.

Compared with the infected group, the survival rate of the SH-treated group was significantly higher in the experimental model of Galleria mellonella caterpillars Wu et al. In addition, our previous investigation also found that sodium new houttuyfonate SNH , which were modified compounds of SH, had a marked antifungal effect on A.

SNH achieves antifungal effects by inhibiting the synthesis of ergosterol in the cell membrane of A. In addition, in a mouse model of systemic A. fumigatus infection, SNH treatment significantly reduced the fungal load in the tissues Zhang et al. Studies have also found that essential oils can synergistically improve the antifungal effect when combined with existing antifungal drugs.

For example, the combination of oregano essential oil and winter savory essential oil with the synthetic antifungal drug clotrimazole significantly reduced the metabolic activity of C.

At the same time, low concentrations of winter savory essential oil combined with clotrimazole caused organellar disorder in this fungus, with autophagic vacuoles, whereas high concentrations of winter savory essential oil combined with clotrimazole caused complete destruction of C.

glabrata organelles Massa et al. Recent investigations have also reported that peppermint essential oil could alleviate the excessive inflammation exhibited by LPS-induced RAW It also found that the essential oil from Citrus flower blocked the MAPK signaling pathway by inhibiting the phosphorylation of p38 and JNK and downregulating the gene expression of IL-6 , IL-1β , and TNF-α in RAW Like dexamethasone, 1-h early injection of lavender essential oil had a therapeutic effect in the rat model of kappa-carrageenan-induced pleurisy.

Further research found that the volume and total protein concentration of the exudate collected from the rats were both significantly reduced, while the total numbers of leukocytes and polymorphocytic leukocytes migrating into the pleural cavity were also reduced Silva et al.

This phenomenon also occurred in an animal model of carrageenan-induced pleurisy treated with rosemary essential oil. Investigations found that rosemary essential oil could induce leukocyte migration in vivo as well as induce chemotaxis in vitro.

Recent studies found that dietary supplementation of rosemary essential oil significantly reduced MPO activity and IL-6 level in a 2,3,6-trinitrobenzenesulfonic acid TNBS -induced colitis mouse model Borges et al.

The effect of Citrus bergamia bergamot orange essential oil on acne vulgaris was explored in the Mesocricetus auratus golden hamster model. It was found that the serum levels of IL-1α and TNF-α decreased in response to the oil in a dose-dependent manner after treatment Sun et al.

Moreover, intragastric administration of SNH could significantly reduce fungal load in tissues and exerted anti-inflammatory effects through downregulating the production of inflammatory cytokines IL-6 and ILA in a mouse model of systemic A.

fumigatus infection Zhang et al. Peppermint essential oil has marked anti-inflammatory effect, not only inhibiting NO and PGE2 production in LPS-activated RAW Because of the antifungal potential of some essential oils when used alone or in combination, and of the efficacy of some essential oils in regulating inflammation, plant-derived essential oils also have great development potential in antifungal applications.

This review first briefly summarizes the current situation of clinical antifungal treatments of common superficial and deep fungal infections, the antifungal mechanisms of existing antifungal drugs Fig. At present, although there are few types of antifungal drugs and their targets, antifungal drugs can better help treat fungal infections by regulating the secretion of pro-inflammatory or anti-inflammatory factors to regulate the immune function of the host.

So, can plant secondary metabolites cause similar effects? The mode of action of different antifungal plant secondary metabolites against various pathogenic fungi and the immunomodulatory effects of plant metabolites on the host were further reviewed.

The antifungal mechanisms of plant secondary metabolites primarily include 1 inhibition of fungal mycotoxin synthesis; 2 prevention of fungal biofilm formation and destruction of the established fungal biofilm; 3 decrease in the number of spores and the growth of hyphae; 4 prevention of ergosterol synthesis, disruption of cell membrane permeability, and promotion of cell wall destruction and lysis; and 5 alteration of cellular DNA replication and disruption of the cell cycle Fig.

At the same time, it was found that many plant secondary metabolites also reduced tissue inflammation and played an immunoregulatory function by reducing the release of pro-inflammatory factors Table 2. In summary, many plant secondary metabolites have both antifungal and immunomodulatory effect Fig.

And most of them have been used in clinical therapy independently or combined with existing antifungal drugs to better exert antifungal effects Table 3. Therefore, plant secondary metabolites have broad prospects for the development of novel antifungal drugs. Mechanism of antifungal action of existing antifungal drugs and plant secondary metabolites.

A Antifungal targets had been confirmed in the existing antifungal drug. Existing antifungal agents include allylamines, azoles, polyalenes, echinocins, and flucytosine. B Antifungal targets had been confirmed in the plant secondary metabolites.

The antifungal pathway of plant secondary metabolites include 1 prevention of fungal biofilm formation and destruction of the established fungal biofilm; 2 alteration of cellular DNA replication and disruption of the cell cycle; 3 inhibition of fungal mycotoxin synthesis; 4 prevention of ergosterol synthesis, disruption of cell membrane permeability, and promotion of cell wall destruction and lysis; and 5 decrease in the number of spores and the growth of hyphae.

Summary of plant secondary metabolites with both antifungal and immunomodulatory effect. These compounds are derived from alkaloids, phenols, terpenoids, and other plant secondary metabolites, respectively. There are an estimated , plant species in nature, and some of them have been used as traditional herbal medicines to treat diseases since ancient times Wang et al.

Generally, plant extracts are complex mixtures, and their active ingredients vary according to plant species, chemical types, and extraction methods. Each ingredient may have multiple targets in the body. Therefore, it is still necessary to explore the specific mechanisms of individual antifungal plant metabolites against fungi or for immunoregulation in vivo.

Additionally, the development of antifungal and immunomodulatory drugs from plant secondary metabolites is still at the preliminary stage. The available clinical references are extremely scarce, and such drugs are still a long way from being used in the clinic. Therefore, what techniques should be used to extract plant secondary metabolites, which secondary metabolites have antifungal or broad-spectrum antifungal effects, how do they affect the immune status of the host body, and can they be used as antifungal or immunomodulatory drugs in clinical?

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Also, 10 was reported as a secondary metabolite of a P. citrinum strain The structures of the metabolites produced by P. citrinum are represented in Fig. Chemical structures of secondary metabolites produced by P.

citrinum during chemical warfare against P. digitatum : citrinadin A 6 , deoxycitrinadin A 7 and chrysogenamide A We investigated the antifungal activity of the metabolites produced in the co-culture and P. digitatum was inoculated in agar media containing co-culture extract.

digitatum radial growth Fig. S35 , indicating that the metabolites involved in the fungal warfare have potential as antifungal agents.

digitatum radial growth, respectively, when compared to control Fig. Citrinadins were found to be involved in the response of P. citrinum against other microorganisms in co-cultures, but the biological role of them in biological environments are still unknown to this date Compound 6 was tested for Anti-buruli ulcer activity on Mycobacterium ulcerans MN, but no interesting MIC was observed 43 ; also, cytotoxicity activity of 6 against leukemia and carcinoma cells was reported Our results are the first report of an antimicrobial activity of citrinadins in literature and can provide first insights about the biological role of these compounds in fungal-fungal interactions.

In addition, chrysogenamide A was never reported as an antimicrobial agent until now. Compound 10 exhibited a protective effect on neurocytes against oxidative stress-induced cell death 41 , however no other biological activity for 10 was reported in the literature.

Antifungal assays applying D -Phe- L -Val- D -Val- L -Tyr revealed that this tetrapeptide has inhibitory activity against B. subitllis and the soybean phytopathogen Fusarium virguliforme In contrast, no inhibition of E.

coli , B. subtilis and S. cerevisiae in presence of D -Phe- L -Val- D -Val- L -Tyr or D -Phe- L -Val- D -Val- L -Phe was observed The antifungal activity of the tryptoquialanines was also evaluated, since these compounds seemed to be a chemical response of P.

digitatum against P. citrinum in the chemical warfare. Tryptoquialanines 1 and 4 were tested and revealed an antifungal activity against P. citrinum spore production Fig.

To the best of our knowledge, it is the first report of an antimicrobial activity of the tryptoquialanines. Recently, 1 was demonstrated as an insecticidal compound against Ae. aegypti larvae 23 ; the antifungal activity can provide more understanding about the role of the tryptoquialanines in the citrus-pathogen environment once these compounds are not required for P.

digitatum virulence To investigate the action of the secondary metabolites during the fungal interaction, co-culture samples were stained with Congo Red and observed through confocal laser scanning microscopy. Congo Red is commonly used to stain polysaccharides containing β 1,4 linkages as, by example, the fungal cell wall component chitin 45 , digitatum hyphae were observed in the confrontation zone sample and compared with hyphae distant to the interface region control Fig.

Control hyphae were homogeneous stained with Congo Red while hyphae in the interface region exhibited an altered staining pattern Fig. Similar staining patterns were obtained for knockout mutant fungi which the deleted genes had a role in cell wall organization; as result, mutants exhibited defective cell walls and irregular staining 25 , 46 , Yet, abnormal staining with Calcofluor White was observed for P.

Confocal laser scanning microscopy of Congo Red-stained P. digitatum hyphae A distant from P. citrinum and B in the zone of confrontation. Patches of Congo Red indicates a defective fungal cell wall. This data shows that P.

digitatum hyphae, in contact with the metabolites diffused during the co-culture, have a defective cell wall since Congo Red bounds to fungal cell wall structures. The fungal cell wall is an attractive target of antimicrobials because they are not present in mammalian cells 49 , In conclusion, the microscopy analysis and the antifungal assays reinforce that the metabolites involved in the fungal interaction have potential as antifungal agents and may be the mechanism in nature that these phytopathogens developed to compete against other microorganisms for the host Fig.

Chemical warfare between P. digitatum in citrus fruit. Tryptoquialanines, citrinadins, chrysogenamide A, tetrapeptides and other metabolites are involved in the long-distance inhibition observed.

The search for new natural antimicrobials is a promising field in natural products research concerning the economic impact of postharvest diseases to worldwide agriculture. Furthermore, the appearance of fungi strains resistant to fungicides makes the discovery of new antifungal agents to replace synthetic compounds extremely important.

Using co-cultivation between phytopathogens that compete for the same host, P. citrinum , we observed a fungal interaction. Through MSI technique, we detected secondary metabolites diffused to the interface zone between the microorganisms.

Tryptoquialanines, citrinadins, chyrsogenamide A and tetrapeptides exhibited great antifungal activity, confirming that co-cultures and MSI technique are a good combination in the search of new natural antimicrobials.

Until this date, there has been no information about the interaction between citrus pathogenic fungi. Our data revealed compounds that play a role in the citrus microbial ecology. In addition, we demonstrated that the metabolites studied have great potential as antifungal agents since fungal cell walls are one of the main targets of antifungal compounds.

The use of the identified compounds as natural antifungals instead of synthetic fungicides should be further investigated. This paper opens new research possibilities and contributes to the environmental and human health, helping in the search of safer strategies for agriculture through the use of compounds obtained from natural sources.

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We would like to thank Dr. Katia Kupper for the P. citrinum strain, Dr. Marcos Nogueira Eberlin for the orbitrap mass spectrometer and Guerline François.

Institute of Chemistry, University of Campinas, CP , , Campinas, SP, Brazil. Center for Natural and Human Sciences, Federal University of ABC, , Santo André, SP, Brazil. Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology — Hans Knöll Institute, Jena, Germany.

Chair of Natural Product Chemistry, Friedrich Schiller University Jena, , Jena, Germany. You can also search for this author in PubMed Google Scholar. and C. wrote the manuscript. A and C. performed the MSI analysis.

W analyzed MSI data, isolated and characterized the secondary metabolites, performed the antimicrobial assays and conducted microscopy analysis. oversaw the project. reviewed the manuscript. and J. submitted the manuscript. Correspondence to Taícia Pacheco Fill. Open Access This article is licensed under a Creative Commons Attribution 4.

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Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. nature scientific reports articles article. Download PDF. Subjects Antifungal agents Fungi. Abstract Numerous postharvest diseases have been reported that cause substantial losses of citrus fruits worldwide.

Materials and Methods Fungi culture The P. Extraction of metabolites from the co-culture experiments The whole contents of the co-culture in vitro were cut into small pieces and transferred to an Erlenmeyer flask. Mass Spectrometry analysis MS Extracts were diluted in methanol and analyzed on a Thermo Scientific QExactive ® Hybrid Quadrupole-Orbitrap Mass Spectrometer.