Biocontrol of Candida albicans by Antagonistic Microorganisms and Bioactive Compounds

Candida albicans is an endogenous opportunistic pathogenic fungus that is harmless when the host system remains stable. However, C. albicans could seriously threaten human life and health when the body’s immune function declines or the normal flora is out of balance. Due to the increasing resistance of candidiasis to existing drugs, it is important to find new strategies to help treat this type of systemic fungal disease. Biological control is considered as a promising strategy which is more friendly and safer. In this review, we compare the bacteriostatic behavior of different antagonistic microorganisms (bacteria and fungi) against C. albicans. In addition, natural products with unique structures have attracted researchers’ attention. Therefore, the bioactive nature products produced by different microorganisms and their possible inhibitory mechanisms are also reviewed. The application of biological control strategies and the discovery of new compounds with antifungal activity will reduce the resistance of C. albicans, thereby promoting the development of novel diverse antifungal drugs.


Introduction
Fungal infection is a common global problem affecting humans and its incidence is on the rise [1]. Among them, Candida has been a life-threatening pathogen for a long time, accounting for almost 80% of fungal infections. Recently C. albicans infection causes more than 400,000 cases of blood infection each year, with a mortality rate of about 42% [2][3][4]. C. albicans, a small number in the normal body, is a part of healthy flora. It can exist in the oral cavity, intestinal tract, upper respiratory tract, and other parts. When growing in the state of unicellular yeast cells, it does not cause disease. However, when the normal flora interacts with each other out of balance or the body's immune function and defenses decline, C. albicans proliferates and grows into hyphae, invading cells and causing disease. It has been a major cause of morbidity and mortality in immunocompromised populations [5].
In host, the pathogenicity of C. albicans is caused by the decline of immune function, the change of conventional flora and the destruction of the epithelial protective barrier. During infection, the formation of C. albicans biofilm and the morphological switch from yeast-like to hyphal-like are considered to be two significant pathogenic characteristics of C. albicans. First of all, its morphological plasticity is crucial to the pathogenicity of fungi, as the hyphal form has a key role in the infection process [6][7][8]. In addition, the pathogenicity of Candida is greatly enhanced by the formation of biofilms [9]. Biofilms are microbial communities that irreversibly attach to surfaces. Biofilms behave very differently from planktonic cells, and once formed, they can increase resistance to existing antibiotics and immune responses [10]. Therefore, inhibition of hyphal development and inhibition of biofilm formation are considered to be an effective strategy against C. albicans infection.
Currently, there are very few drugs for the treatment and prevention of Candidiasis in clinic. The polyene antibiotic is the earliest specific drug isolated from Streptomyces nodosus in the 1950s to treat yeast infection. Since then, many antifungal agents have been developed [11,12]. There are four types of antifungal agents for C. albicans infection [13]. The most commonly used antifungal drugs and the mechanism of action include:(1) The widest range and most effective is polyene (Amphotericin B), which can kill most fungi. Polyenes bind to ergosterol in fungal cell membranes, creating stomata and causing cell death [14,15]. (2) Triazole antifungal drugs (fluconazole, voriconazole and itraconazole). Azoles can inhibit lanosterol 14α demethylase, which is an important enzyme in ergosterol biosynthesis [16][17][18][19]. (3) 5-fluorocytosine, it inhibits fungal DNA synthesis by inhibiting thymidylate synthetase [12,20]. (4) There are also some echinocandin antifungal drugs (anidulafungin, micafungin, and caspofungin) [21][22][23][24][25][26][27]. The mechanisms of these bioactive compounds against C. albicans are mainly related to inhibition of biofilm formation, inhibition of virulence factors and destruction of cell wall integrity. With the increasing drug resistance of C. albicans, it is compelling to find new antifungal methods and reagents to solve this complex medical problem. Biological control is considered to be a more effective and safe strategy [1,28,29].
Novel natural compounds produced by microorganisms, due to their complex structures, may exhibit novel antibacterial mechanisms and different modes of action. Moreover, they were considered as candidates to reduce drug resistance. People have been trying to find unique antifungal drugs from nature, which has led to important advances in the development of new antifungal drugs.
In recent years, there have been some reviews on natural products that could inhibit C. albicans [2,[30][31][32][33][34][35][36][37]. In this paper, we have reviewed the antagonistic microorganisms against C. albicans considered in recent years and have also reviewed the active natural products produced by microorganisms that inhibit C. albicans. Researchers focus on the study of antagonistic microorganisms in order to use probiotics to inhibit C. albicans. Through the review of secondary metabolites, it can provide a reference for clinical drug development.

Antagonistic Microbes against C. albicans
Traditional azoles and their derivatives have poor effect on preventing recurrence of pathogenic fungus. In some patients, fluconazole can cause some side effects such as headache, discomfort, dizziness, gastrointestinal and, rash [38]. Bacteria, yeast, and fungus all can develop resistance to antibiotics and bactericidal chemicals [39]. Biological control of microbial infections is an alternative approach that utilizes antagonistic microorganisms to prevent the growth and infection of harmful microorganisms. Diverse microorganisms, including fungi (such as non-toxic Aspergillus, Trichoderma, Penicillium), yeast strains, and bacteria, have been studied as potential antagonistic organisms for the control of C. albicans. In this review, the microorganisms that inhibit C. albicans and their secondary metabolites are introduced from the perspective of antagonistic microorganisms. The microorganisms that have potential antagonism against C. albicans are listed in Table 1. The main species and inhibition activities of these antagonistic strains are also discussed. We have reviewed the antagonistic microorganisms against C. albicans in recent years with the aim to develop a new natural material, using beneficial bacteria or fungus, that would be useful for inhibiting the growth of pathogenic C. albicans in the human body.

Enterococcus
Regulated growth and virulence of C. albicans through niche competition. [48]

Salivarius MG242
The strain had significant inhibitory effect on C. albicans. [50] B.brevis T122 B.subtilis spizizenii DK1-SA11 Cell-free supernatant had significant inhibitory activity against C. albicans. [41] B. velezensis DTU001 Significantly inhibited the proliferation of C. albicans, and the inhibition ability of the strain was better than that of a single lipopeptide. [42] B.amyloliquefaciens SYBC H47 Cell-free supernatant and Cell suspension had obvious inhibition against C. albicans. [43] B. velezensis 1B-23 Inhibited C. albicans growth in vitro. [44] B. longum BB536 The supernatant of fermented broccoli could inhibit the growth of C. albicans in vitro. [45,46] L. johnsonii MT4 Inhibited planktonic growth and biofilm formation of C. albicans [47] Lactobacillus Regulated growth and virulence of C. albicans through niche competition. [48] Metschnikowia pulcherrima Strong antagonistic activity against C. albicans [49] Enterococcus Regulated growth and virulence of C. albicans through niche competition. [48]

Antagonistic Effect of Bacillus spp. against C. albicans
Some beneficial bacteria or fungus are widely used in biocontrol. In particular, it is well known that Bacillus spp. is an excellent source of antifungal drugs, thus Bacillus spp. Some beneficial bacteria or fungus are widely used in biocontrol. In particular, it is well known that Bacillus spp. is an excellent source of antifungal drugs, thus Bacillus spp. is widely used as a biological control agent [51][52][53]. Bacillus species are Gram-positive bacteria that can survive in different environments. They could form endospores and produce a large number of metabolites [53]. Researchers isolated four strains of Bacillus A16 (B. sphaericus), M142 (B. circulans), M166 (B. brevis) and T122 (B. brevis) from soil samples. These Bacillus showed extensive inhibitory activity against C. albicans [40]. Among them, B. brevis M166 showed antifungal activity against all tested microorganisms (Sclerotium rolfsii, Rhizoctonia solani, Fusarium oxysporum, Staphylococcus aureus and C. albicans), with a relatively wide antimicrobial spectrum. B. circulans M142 had strong antibacterial activity against C. albicans and S. aureus, while B. brevis T122 only had antibacterial activity against C. albicans. To our knowledge, no specific compounds inhibiting C. albicans had been identified.
In addition to the antifungal activity of Bacillus spp. from soil samples, Bacillus spp. from marine samples was also found to have inhibitory activity against C. albicans. B. subtilis spizizenii DK1-SA11 was isolated from Bay of Yellow Sea in China [41]. The cellfree supernatant had significant inhibitory activity against C. albicans. The inhibitory active ingredient had not been identified but was stable in nature, while the enzymatic hydrolysis of lipase, trypsin and papain made it lose activity. Antimicrobial activity tests against pathogens indicated that this strain could be used as a source of antibiotics, synbiotics, and probiotics.
B. velezensis was widespread in the environments and produced abundant lipopeptides with good bacteriostatic effect. Some researchers have studied on the inhibitory spectrum of B. velezensis DTU001 against 20 different species of human and/or plant pathogenic fungi [42]. The results showed that B. velezensis DTU001 was superior to a single lipopeptide (fengycin and iturin) in inhibiting the selected fungi. Co-culture of B. velezensis DTU001 and C. albicans significantly inhibited C. albicans proliferation, which further supported the biological control properties of B. velezensis DTU001.
B. amyloliquefaciens SYBC H47 was isolated from honey [43]. The cultured cell-free supernatant had significant inhibitory activity against C. albicans. The main antibacterial substances were surfactin, fengycin and bacillomycin. Three compounds had an inhibitory effect on spore germination of Botryosphaeria dothidea. However, compounds that inhibit C. albicans had not been identified.
Bacillus velezensis 1B-23 had inhibitory effect on the growth of C. albicans in vitro. It had a certain application prospect as a biological agent for biological control of fungal pathogens [44].

Antagonistic Effect of Bifidobacterium spp. against C. albicans
Bacillus spp. has been used clinically because of its bacteriostatic activity. Another probiotic, Bifidobacterium, can also be used to prevent and treat intestinal flora disorders in clinic. Bifidobacterium is a vital member of the normal human gut microbiota. Some strains of Bifidobacterium can be used as probiotics in food, medicine and feed [54,55]. Bifidobacteria could produce acetic acid and/or lactic acid during metabolism. Moreover, the action of lactic acid would reduce intestinal pH. Thereby, Bifidobacterium could inhibit the proliferation of pathogenic microorganisms [56,57].
Bifidobacterium longum BB536 which was isolated from the feces of healthy infants had been commercially used in various food applications and was considered safe [45,46,58]. The researchers fermented broccoli using B. longum. The supernatant could inhibit the growth of C. albicans and some other pathogenic bacteria in vitro. Researchers used beneficial bacteria such as bifidobacteria and used broccoli as a substrate for the growth of beneficial bacteria to develop substances. Maybe, we can use beneficial microorganisms and their secondary metabolites to develop products that inhibit the growth of pathogenic microorganisms. For example, as a daily oral care preparation, it can prevent the growth of C. albicans in human oral cavity [59].

Antagonistic Effect of Lactobacillus spp. against C. albicans
Lactobacillus johnsonii is a probiotic with wide antimicrobial characteristics and can be used as an antiallergic drug. Recent studies have shown that L. johnsonii also has inhibitory effects on C. albicans. L. johnsonii MT4 was isolated from the oral cavity of healthy mice. The strain affected the C. albicans growth in both biofilm and planktonic conditions. L. johnsonii MT4 showed an antagonistic effect on C. albicans, thus inhibiting the biofilm formation of C. albicans and planktonic growth. The study on the strain genome had shown that it produced metabolites with anti-C. albicans activity, but no active substances against fungi have been reported so far. The antibacterial mechanism needed to be further explored [47].
In addition to producing secondary metabolites that antagonize C. albicans, the competition for ecological niches of different strains during the growth process would also cause antagonism among strains, such as C. albicans and lactic acid bacteria in the gastrointestinal (GI) tract [48,60]. Non-pathogenic colonization of the human GI tract by C. albicans was common. C. albicans could regulate bacterial community in mice treated with broadspectrum antibiotics. One of the most striking features was the significant change in the lactic acid bacteria (LAB) levels. C. albicans and Lactobacillus species shared a metabolic niche throughout the GI tract. LAB could antagonize Enterococcus and C. albicans in the GI tract. C. albicans and Lactobacillus could mutually regulate each other's growth and virulence in the GI tract [48].

Antagonistic Effect of Yeast against C. albicans
In addition to the bacteria mentioned above, yeast can also be used for biological control. Metschnikowia could accumulate pigments in cells and growth media. It was a highly effective biocontrol yeast. Antagonism of M. pulcherrima against phytopathogens had been demonstrated [49]. The researcher investigated three new strains of Metschnikowia which were isolated from grapes. The strain had strong antagonistic activity against C. albicans. The three strains produced the same amount of nevus pigments, but there were significant differences in antifungal activities against different microorganisms [61,62].

Antagonistic Effect of Other Strains against C. albicans
Salivarius MG242 isolated from human vagina presented a potential application in the biological control of C. albicans. MG242 had an obvious inhibitory impact on C. albicans, and the strain had the possibility to be developed into a probiotic product for the treatment of C. albicans. In order to develop stable living cell products, it was necessary to maintain anti-Candida activity and preserve cell viability during lyophilization. Lower storage temperature extended shelf life to 8.31 months [50]. Strains of K124 (P. fluorescens) was also isolated from soil samples, e.g., B. sphaericus A16, B. circulans M142, B. brevis M166 and B. brevis T122. P. fluorescens K124 showed extensive inhibitory activity against C. albicans [40]. P. fluorescens K124 only had antifungal activity against C. albicans. At present, no inhibitory compounds produced by the strain have been identified.

A Conclusion of Antagonistic Microbes
In conclusion, Bacillus, Bifidobacterium, Lactobacillus, and yeast strains can antagonize the growth of C. albicans. In particular, many strains of Bacillus have obvious advantages to exert antagonistic strains. Most of the strains exert antagonistic effects by producing active compounds. Moreover, some inhibit the growth of C. albicans through niche competition. We should intensify research on strains with inhibitory activity, especially probiotics. Research on different strains, especially probiotics, with antifungal activity is helpful to develop the agent for inhibiting C. albicans. Since the effective components of some strains against C. albicans are not clear, the compounds with obvious inhibitory activity should be further analyzed.

Inhibitory Nature Metabolites Produced by Diverse Antagonists
Secondary metabolites derived from many plants and microorganisms are valuable natural compounds. Many natural products have significant biological activities, such as anti-tumor activity, antibacterial activity [63][64][65]. The antagonistic effect of the strain is mainly due to the production of natural secondary metabolites, such as antibiotics and antimicrobial peptides [66][67][68]. The antifungal compounds reviewed in this paper are Antibiotics 2022, 11, 1238 6 of 18 secondary metabolites derived from microorganisms for biological control of C. albicans and have strong inhibition against C. albicans. Table 2 lists the various antagonistic microbial strains, the characteristics of the active compounds produced, and their inhibition mechanism against C. albicans. Table 3 lists the structure and the activity of these inhibitory compounds. Ustilago maydis Ustilagic acid B and C Inhibit growth None [95] 5HM2F: 5-hydroxymethyl-2-furaldehyde.  Ustilago maydis Ustilagic acid B and C Inhibit growth None [95] 5HM2F: 5-hydroxymethyl-2-furaldehyde. Purpurides E and F The MIC values were 12 and 6 μg/mL, respectively. [80] Usnic acid The MBIC value was 100 μg/mL. [84] The MIC value was 16 µg/mL [77] Purpurides E and F Fusarium spp. Deoxynivalenol Inhibit biofilm formation and reduce metabolic activity DON and its derivatives interplayed with lanosterol 14a-demethylase [93] Penicillium fuscum and Penicillium camembertii/clavigerum Berkleyolactone A Inhibit growth A new mode of action that had not been resolved [94] Ustilago maydis Ustilagic acid B and C Inhibit growth None [95] 5HM2F: 5-hydroxymethyl-2-furaldehyde. Purpurides E and F The MIC values were 12 and 6 μg/mL, respectively. [80] Usnic acid The MBIC value was 100 μg/mL. [84] The MIC values were 12 and 6 µg/mL, respectively. [80] Usnic acid reduce metabolic activity 14a-demethylase Penicillium fuscum and Penicillium camembertii/clavigerum Berkleyolactone A Inhibit growth A new mode of action that had not been resolved [94] Ustilago maydis Ustilagic acid B and C Inhibit growth None [95] 5HM2F: 5-hydroxymethyl-2-furaldehyde. Macrolides PF1163 A and B The inhibitory concentrations were 1 and 2 μg/mL, respectively. [79] Bahamaolides A The MIC value was 12.5 μg/mL. [82] Berkleyolactone A The MIC value was 1-2 μg/mL. [94] Organic acids

Inhibitory Compounds Compound Structure Activity References
Organic acids

Inhibitory Compounds Compound Structure Activity References
Biatriosporin D

Nature Products Produced by Bacteria
Bacillus produces diverse active compounds, such as proteases, amylases, surfactants, and antibiotics [66,[96][97][98][99]. Due to the high yield of antifungal active substances and the advantage of releasing peptides directly into the extracellular, Bacillus subtilis is a potential strain for the production of antifungal compounds [100][101][102]. The B.subtilis isolated from marine had antifungal membrane effect on C. albicans. It was found that 5-hydroxymethyl-2-furaldehyde (5HM2F) was one of the main components that inhibited C. albicans in the fermentation broth [69]. 5HM2F effectively disrupted the hyphal-like morphological transition of C. albicans and prevented the initial adhesion process. Further studies showed that 5HM2F reduced the main source of biofilms by reducing the levels of secreted virulence factors and ergosterol. In addition, the combination of 5HM2F with azole antifungal drugs effectively enhanced the anti-C. albicans activity of the tested drugs. Transcriptional level studies showed that 5HM2F increased the sensitivity of C. albicans to antifungal drugs by negatively regulating the expression levels of genes related to drug resistance mechanisms. As an antagonist, 5HM2F effectively inhibited the biofilm formation and reduced the resistance of C. albicans to traditional antifungal drugs.
Six novel alkaloids containing phenethylamine (PEA) were isolated from the culture medium of Tenacibaculum discolor sv11. Among them, Dipyrrolepyridines A and B had certain inhibitory activity against C. albicans FH2173 [71].

Nature Products Produced by Bacteria
Bacillus produces diverse active compounds, such as proteases, amylases, surfactants, and antibiotics [66,[96][97][98][99]. Due to the high yield of antifungal active substances and the advantage of releasing peptides directly into the extracellular, Bacillus subtilis is a potential strain for the production of antifungal compounds [100][101][102]. The B.subtilis isolated from marine had antifungal membrane effect on C. albicans. It was found that 5-hydroxymethyl-2-furaldehyde (5HM2F) was one of the main components that inhibited C. albicans in the fermentation broth [69]. 5HM2F effectively disrupted the hyphal-like morphological transition of C. albicans and prevented the initial adhesion process. Further studies showed that 5HM2F reduced the main source of biofilms by reducing the levels of secreted virulence factors and ergosterol. In addition, the combination of 5HM2F with azole antifungal drugs effectively enhanced the anti-C. albicans activity of the tested drugs. Transcriptional level studies showed that 5HM2F increased the sensitivity of C. albicans to antifungal drugs by negatively regulating the expression levels of genes related to drug resistance mechanisms. As an antagonist, 5HM2F effectively inhibited the biofilm formation and reduced the resistance of C. albicans to traditional antifungal drugs.
Six novel alkaloids containing phenethylamine (PEA) were isolated from the culture medium of Tenacibaculum discolor sv11. Among them, Dipyrrolepyridines A and B had certain inhibitory activity against C. albicans FH2173 [71].

Nature Products Produced by Bacteria
Bacillus produces diverse active compounds, such as proteases, amylases, surfactants, and antibiotics [66,[96][97][98][99]. Due to the high yield of antifungal active substances and the advantage of releasing peptides directly into the extracellular, Bacillus subtilis is a potential strain for the production of antifungal compounds [100][101][102]. The B.subtilis isolated from marine had antifungal membrane effect on C. albicans. It was found that 5-hydroxymethyl-2-furaldehyde (5HM2F) was one of the main components that inhibited C. albicans in the fermentation broth [69]. 5HM2F effectively disrupted the hyphal-like morphological transition of C. albicans and prevented the initial adhesion process. Further studies showed that 5HM2F reduced the main source of biofilms by reducing the levels of secreted virulence factors and ergosterol. In addition, the combination of 5HM2F with azole antifungal drugs effectively enhanced the anti-C. albicans activity of the tested drugs. Transcriptional level studies showed that 5HM2F increased the sensitivity of C. albicans to antifungal drugs by negatively regulating the expression levels of genes related to drug resistance mechanisms. As an antagonist, 5HM2F effectively inhibited the biofilm formation and reduced the resistance of C. albicans to traditional antifungal drugs.
Six novel alkaloids containing phenethylamine (PEA) were isolated from the culture medium of Tenacibaculum discolor sv11. Among them, Dipyrrolepyridines A and B had certain inhibitory activity against C. albicans FH2173 [71].

Nature Products Produced by Yeast
The researchers found that S. boulardii had inhibitory activity on C. albicans. The fermentation broth extracts inhibited hyphae formation, adhesion and biofilm development of C. albicans [72]. Further analysis showed that the fermentation broth contained 2-phenylethanol, capric, caprylic and caproic acid. The fermentation broth and the isolated pure compounds were tested for biological activity against C. albicans. Capric acid inhibited hyphae formation in C. albicans and also reduced adhesion and biofilm formation. However, compared with S. boulardii extract, the inhibitory effect on C. albicans was reduced by three times in the case of capric acid alone, so other compounds were contained to inhibit the adhesion of C. albicans. The transcriptional levels of CSH1, INO1, and HWP1 genes were decreased in C. albicans treated with B. boulardii extract and capric acid.

Nature Products Produced by Endophytic Fungi
Biatriosporin D (BD), A phenolic compound, was isolated from Biatriospora spp. [73]. The compound inhibited biofilm formation, hyphal morphogenesis and adhesion of C. albicans. Notably, BD efficiently inhibited hyphal formation at doses lower than MIC value. Further studies showed that BD regulated the Ras1-cAMP-Efg1 pathway through reducing the cAMP level. As a prodrug, BD showed potential action against C. albicans. This provided possible application prospects for BD against clinically opportunistic fungi by targeting fungal virulence.
A fungus Drechmeria sp. was isolated from the roots of Panax notoginseng. Four known analogs and seven new indole diterpenoids, drechmerins A-G, were isolated from the fermentation broth. The MIC value of Drechmerin B against C. albicans was 12.5 µg/mL [74].
Three new monomers were isolated from the marine strain Stachybotrys Chartarum. The MIC value of compound Atranone Q was 8 µg/mL [76].
Nine sesquiterpenes and three diterpenes were isolated from the fermentation broth of the Xylaria sp. YM 311647 [77]. The MIC values of nine sesquiterpenes against C. albicans were different, while the activity of diterpenes was higher. One of the sesquiterpenes had the highest antibacterial activity against C. albicans, with an MIC value 16 µg/mL.

Nature Products Produced by Marine Fungi
One of the prenylated indole alkaloids, waikialoid A, was isolated from a metaboliterich Aspergillus strain near Waikiki Beach. IC 50 value of the natural product was 1.4 µM in inhibiting biofilm formation. Another compound, waikialide A, could inhibit the formation of C. albicans biofilm with a weaker IC 50 value of 32.4 µM [78].
Two new 13-membered macrolide compounds and known PF1163A, B, D, H and F were isolated from penicillium strain. All of them had inhibitory activity against C. albicans when used in conjunction with fluconazole [79].

Nature Products Produced by Marine Source Actinomycetes
One new phenylpyridinealkaloid, five known analogues and five new bipyridine alkaloids were isolated from Actinoalloteichus cyanogriseus WH1-2216-6. The MICs of caerulomycin A and C against C. albicans were 21.8 and 19.3 µM, respectively [81].
Two new 36-membered macrolides, Bahamaolides A and B, were isolated from sediments of marine actinomycetes (Streptomyces sp.) on the North Cat Reef, Bahamas. Bahamaolides A obviously inhibited isocitrate lyase of C. albicans [82].
Streptovitacin A and new Streptoglutarimides A-J were isolated from marine actinomycetes Streptomyces sp. ZZ741. The MIC values of the obtained compounds against C. albicans were 8-20 µg/mL, and Streptoglutarimides D had a better inhibitory effect with 8 µg/mL [83].

Nature Products Produced by Lichen
Usnic acid, a secondary metabolite of lichens, effectively inhibited the hyphal switching of C. albicans. Usnic acid significantly reduced the thickness of mature biofilms and prevented the adhesion of biofilms. At the biofilm inhibitory concentration (BIC), the inhibitory effect of usnic acid on C. albicans biofilm could reach 65% [84].
As an inhibitor, Retigeric acid B (RAB) derived from lichen significantly inhibited the hyphae formation of C. albicans [105][106][107]. RAB prolonged the survival time of nematodes infected by C. albicans. RAB regulated the Ras1-CAMP-Efg1 pathway by reducing cAMP levels and inhibitd hyphal formation. By inhibiting the interruption of yeast-hyphal morphological transition and weakening the virulence of C. albicans, it provided a potential application for the treatment of C. albicans infection [85].

Nature Products Produced by Other Fungal Sources
8-deoxytrichothecin and trichodermol, isolated from the Acremonium sp. PSU-MA70, exhibited moderate antifungal activity against C. albicans [87]. Two compounds cyschalasins A and B were isolated from Aspergillus Micronesiensis and showed antifungal activity against C. albicans [88]. Moriniafungins B-G, a new tetracyclic diterpene glycoside of Sordarincin, was isolated from Curvularia hawaiiensis TA26-15. Moriniafungins B-G had antifungal activity against C. albicans with an MIC value of 2.9 µM [89].
The F2 mycotoxin zearalenone (ZEN) produced by Fusarium and Gibberella species exhibited in vitro inhibitory effects on different microbial strains [90,91]. 100 µg/mL ZEN treatment significantly inhibited C. albicans hyphal morphogenesis and biofilm formation. Similarly, ZEN effectively destroyed established C. albicans biofilms without disturbing the planktonic cells. In vivo, ZEN prominently inhibited C. albicans infection in Caenorhabditis elegans [92].
Deoxynivalenol (DON), produced by Fusarium spp., was an epoxide sesquiterpene compound [93,[108][109][110]. DON and 3-acetyl-DON exhibited a dose-dependent inhibitory effect on C. albicans in vitro. DON obviously reduced C. albicans metabolic activity, disrupted pre-formed biofilms, inhibited biofilm formation and inhibited hyphal that embedded in free-living planktonic cells and colonies. DON and 3-acetyl-DON mimicked the mechanism of through interplaying with lanosterol 14α-demethylase that was like the action of azole drugs. DON exhibited antifungal filament and antifungal membrane potential against C. albicans [111].
A carefully scheduled fermentation of P. camembertii/clavigerum and P. fuscum yielded eight novel 16-membered ring macrolides, Berkelilactone A exhibited the most potent antifungal activity in the macrolide series. It had low micromolar inhibitory activity against C. albicans (MIC = 1-2 µg/mL). Berkelilactone A did not inhibit protein synthesis and did not target ribosomes, suggesting a new mode of mechanism for its antibiotic activity, but the specific mechanism had not yet been elucidated [94].
U. maydis secreted a large amount of the glycolipid biosurfactant ustilagic acid. The new glycolipid ustilagic acid C and B were induced under special culture conditions. And the two compounds showed weak antifungal activity against C. albicans [95].

A Conclusion of Inhibitory Compounds Produced by Antagonistic Microbes
Many natural products that obtained from diverse microbial sources have been successfully applied in many fields. To overcome the increasing drug resistance of C. albicans, the discovery of new natural antifungal compounds is necessary. This review summarizes about 30 different compounds produced by microorganisms that have been found to have inhibitory effects on C. albicans. These compounds are derived from different bacteria and fungi, including bacteria such as Bacillus, T. discolor sv11 and P. agglomerans; yeast such as S. bombicola and S. boulardii; Phoma spp. SYSU-SK-7, Biatriospora sp.; marine-derived fungi such as Aspergillus, P. minioluteum ZZ1657; Streptomyces sp.; A. cyanogriseus WH1-2216-6; Streptomyces sp. ZZ741 and Actinomycetes of marine origin; other fungal sources: Fusarium, Gibberella species, P. brown, P. camembertii/clavigerum, C. Hawaiian ensis TA26-15, U. maydis; A. micronesiensis, Acremonium sp. PSU-MA70 and other fungi. It can be seen from Table 2 that the antifungal mechanisms of most isolated known or unknown compounds have not been clearly analyzed. Only a few compounds have been studied at the transcriptional level. These microorganisms produce compounds with different structures to inhibit C. albicans in different ways, such as inhibiting biofilm formation and hyphal morphological transformation.

Conclusions
With the emergence of C. albicans resistance against conventional antifungal therapies, new strategies to treat C. albicans infection are important [112]. Considering that C. albicans could threaten human life and health when the body's immune function declines or the normal flora is out of balance. both Bacillus licheniformis and Bifidobacterium can be used in clinic to prevent and treat intestinal microbiota disorders. This article reviews the different antagonistic microorganisms of C. albicans and various bioactive secondary metabolites produced by microorganisms, which are expected to achieve biological control of human pathogenic fungus C. albicans.
Biological control of microbial infections is an alternative approach that utilizes antagonistic microorganisms to prevent the growth and infection of harmful microorganisms. Antagonistic microbes, such as bacteria, yeast, and fungus, have been studied as potential antagonistic organisms for the control of C. albicans. Through the study on diverse strains with antifungal activity, it is helpful to develop the agent for inhibiting C. albicans. This is a potential strategy for biological control of C. albicans. On the other hand, secondary metabolites derived from microorganisms are valuable natural compounds. Many natural products have diverse structures and can exhibit significant biological activities. The structures of these compounds include: macrolides, terpenoids, alkaloids, organic acids, and other heterocyclic compounds. The secondary metabolites introduced in Tables 2 and 3 can significantly inhibit C. albicans. They are produced by diverse microorganisms. However no identified compounds are currently used as a drug against C. albicans. There are still four types of antifungal agents for C. albicans infection: polyene, triazole, 5-fluorocytosine, and echinocandin antifungal drugs [13]. Through the study of these active compounds, it is expected to obtain new drugs for the treatment and prevention of C. albicans infection, thereby maintaining human health.