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Review

Strategies for Supplying Precursors to Enhance the Production of Secondary Metabolites in Solid-State Fermentation

1
Biotechnology Department DCBS, UAM-I, San Rafael Atlixco No. 186, Col. Vicentina, Mexico City 09340, Mexico
2
Laboratorio de Microbiología, Unidad Académica Multidisciplinaria Mante, Universidad Autónoma de Tamaulipas, El Mante 89840, Mexico
3
Departamento de Ingenierías Química y Bioquímica, Tecnológico Nacional de México/IT Durango, Blvd. Felipe Pescador 1830 Ote., Durango 34080, Mexico
*
Author to whom correspondence should be addressed.
Fermentation 2023, 9(9), 804; https://doi.org/10.3390/fermentation9090804
Submission received: 28 July 2023 / Revised: 22 August 2023 / Accepted: 30 August 2023 / Published: 31 August 2023
(This article belongs to the Special Issue New Trends in Solid Fermentation)

Abstract

:
The production of secondary metabolites can be improved with the supply of precursors both in submerged and solid-state fermentation (SSF). Microorganisms assimilate the precursors and biotransform them to excrete compounds of commercial interest. The raw materials used in SSF, frequently agro-industrial residues, may contain molecules that serve as precursors for secondary metabolites. However, supplying a precursor can dramatically improve crop production. Commonly, precursors are added as part of the liquid with which the solid material to be fermented is moistened. However, recently it has been proposed to take advantage of the oxygen supply for the gradual supply of volatile precursors. It can help to avoid toxicity problems with the precursors. The present work reviews the strategies to supply precursors to improve the production of secondary metabolites in solid-state fermentation.

1. Introduction

Microbial secondary metabolites are low-molecular-weight compounds synthesized by microorganisms after the growth phase. Secondary metabolites are not directly involved in microbial growth. Still, they play a significant role in competition, antagonism, and self-defense mechanisms [1]. These compounds have a variety of chemical structures, and many have biological activities such as antimicrobial, antiviral, antioxidant, antitumor, vasodilator, vasoconstrictor, diuretic, and laxative activities, among others [2]. Utilizing microbial cultures for secondary metabolite production has proven to be an effective strategy for reducing production costs and carbon footprints. Moreover, microbial production also contributes to preserving plant biodiversity [3] since microorganisms can produce some plant secondary metabolites through the biotransformation of precursors. Microbial production then allows humans to avoid the disadvantages of plant extraction, like low yield, which leads to plant over-exploitation.
Production of microbial secondary metabolites is influenced by diverse culture conditions such as the composition of culture media, the carbon/nitrogen ratio, salinity, the presence of metal ions, temperature, pH, and oxygen concentration [4]. The fermentation system significantly influences the production of secondary metabolites. They are mainly produced by submerged fermentation (SmF) due to the ease of measuring, monitoring, and controlling process variables. Nonetheless, solid-state fermentation (SSF) is recognized to imitate the natural environment for the growth of microorganisms, representing an advantage for obtaining some metabolites [5].
SSF is a process whereby microorganisms grow in the absence of free water or with low water content [6]. It has been used since ancient times to obtain fermented foods such as koji, bread, and cheeses. Even in the last century, SSF has produced compounds for the food, pharmaceutical, textile, biochemical, and energy industries [7]. This innovative culture system has produced a wide range of secondary metabolites, including bioactive compounds, enzymes, polyphenols, food additives, and others [8,9,10].
There are two types of SSF. The first is the most common and uses a natural solid material acting as substrate and support. The second uses an inert support impregnated with a nutritive culture medium. In both systems, advantages of SSF over SmF have been reported, such as higher yield in the production of enzymes and secondary metabolites. Furthermore, some microorganisms only produce certain enzymes or secondary metabolites in SSF, even though they can grow well in SmF [11]. Therefore, different authors have used SSF to produce pigments, antibiotics, statins, biosurfactants, phenolic compounds, and other secondary metabolites. Table 1 shows some examples of secondary metabolites that SSF can obtain.
Fungal pigments are probably the first secondary metabolites commercially produced by SSF. Fungi of the genus Monascus have been cultivated on cooked rice in Asian countries since ancient times to make a red colorant known as “Anka,” or “red mold rice,” which is used as a food ingredient [46]. Monascus sp. produces orange, red, and yellow pigments in these conditions. These pigments are a mixture of secondary metabolites such as monascin, ankaflavin, rubropunctatin, monascorubrin, rubropunctamin, and monascorubramine, among others [12,13].
Antibiotics are one of the best-known groups of microbial secondary metabolites. Antibiotics act against other microorganisms affecting cellular processes such as DNA replication, transcription, cell wall synthesis, and cell membrane disruption [47]. Antibiotics are produced commercially by SmF. However, SSF is an alternative system with advantages for large-scale production, such as higher yields in shorter periods [11]. For this reason, various authors have investigated the production of antibiotics such as penicillin [14,15], cephalosporin C [16,17], paramomycin [18], neomycin [19], and rifamycin [20] by SSF.
On the other hand, statins are a group of drugs that lower blood cholesterol levels, decreasing the risk of heart attack or stroke. Filamentous fungi produce natural statins (lovastatin, compactin, and monacolin K). Notably, the industrial production of lovastatin is mainly carried out by SmF using Aspergillus terreus [48]. However, several authors have described the advantages of SSF for lovastatin production compared to SmF. For example, Baños et al. [24] reported 30 times higher lovastatin production by A. terreus TUB F-514 in SSF than in SmF. In addition, the specific production was 14 times higher in SSF. Therefore, the Indian biotech company Biocon Ltd. developed a method to produce lovastatin in SSF using the Plafractor bioreactor [49]. Lovastatin produced by SSF received FDA approval for sale in the United States in 2001.
Other molecules produced at the end of the exponential growth phase of certain bacteria, yeasts, and molds are biosurfactants, which reduce surface and interfacial tension due to their amphiphilic nature. These molecules are involved in cell development, biofilm formation, osmotic pressure regulation, and hydrophobic substance assimilation [50]. They are produced by certain microorganisms, mainly by SmF. Still, during their manufacture, a large amount of foam is produced, increasing the risk of contamination and reducing productivity. Conversely, SSF eliminates the foaming problem and reduces energy and water consumption during production [34]. For this reason, different researchers have investigated SSF to produce biosurfactants such as sophorolipids [35,36], rhamnolipids [33,34], surfactin [30,31], and iturin [32], among others.
Some secondary metabolites obtained from plants cannot be produced directly by microorganisms. However, some microorganisms can biotransform the chemical precursors of those plants’ secondary metabolites. For example, vanillin is an essential flavoring agent in the food industry, traditionally extracted from vanilla pods. Several bacteria of the genera Amycolatopsis, Streptomyces, Pseudomonas, Delftia, and Enterobacter can catalyze the conversion of ferulic acid to vanillin. Some authors have investigated the use of ferulic acid-rich agro-industrial by-products such as sugarcane bagasse [37], pomegranate peels [38], and wheat straw [39] to produce biovanillin through SSF.

2. Main Biosynthetic Pathways of Secondary Metabolism

Secondary metabolites are not essential for organisms’ growth, development, reproduction, or energy production. Therefore, these compounds are not produced by all microbial species. Secondary metabolites are synthesized from primary metabolites, such as acetyl-coenzyme A and amino acids, through secondary metabolic pathways [51].
Two metabolic pathways synthesize the precursors of phenolic compounds: the shikimic acid and malonic acid pathways. The shikimic acid pathway is most important in plants. The malonic acid pathway is an essential source of phenolics in fungi and bacteria but is less significant in plants [52]. Terpenoid precursors can be synthesized by two metabolic pathways: the mevalonic acid pathway or the methylerythritol phosphate pathway. The mevalonic acid pathway is present in plants, animals, yeast, fungi, archaea, and some eubacteria. The methylerythritol phosphate pathway is present in most bacteria, cyanobacteria, and plant plastids [53]. Primary and secondary metabolic pathways are interrelated, as shown in Figure 1. The regulation of secondary metabolism is a complex process. Therefore, in order to improve the production of secondary metabolites by microorganisms, it is essential to understand the metabolic pathways involved. The main metabolic pathways related to the production of secondary metabolites in microorganisms are described below.

2.1. Shikimate Pathway

The shikimate pathway provides precursors for aromatic molecules in bacteria, fungi, and plants but not in animals. This pathway provides the aromatic amino acids (L-phenylalanine, L-tyrosine, and L-tryptophan) necessary for protein synthesis. Aromatic amino acids also serve as precursors for secondary metabolites, such as phenolic compounds and some alkaloids [54].
The shikimate pathway consists of seven enzymatic reactions: First, phosphoenolpyruvate (an intermediate metabolite in the Embden–Meyerhof–Parnas pathway) and D-erythrose-4-phosphate (an intermediate metabolite in the pentose phosphate pathway) are converted to 3-deoxy-D-arabino-heptulosonate-7-phosphate (DAHP) by DAHP synthase. DAHP is then converted to shikimic acid by 3-dehydroquinate (DHQ) synthase, DHQ dehydratase, and shikimate dehydrogenase. Last, shikimic acid is converted to chorismic acid by shikimate kinase, 5-enolpyruvylshikimate 3-phosphate synthase, and chorismic acid synthase. The final product of the shikimate pathway (chorismic acid) can be further transformed into aromatic amino acids by a single reaction. [55]. The phenylpropanoid pathway transforms L-tyrosine and L-phenylalanine into various phenolic compounds in higher plants. No evidence exists of complete phenylpropanoid metabolism in organisms other than land plants. However, some homologous enzymes of this pathway have been found in some bacteria and fungi [56].
The shikimate pathway has different metabolic branches in different microorganisms that lead to the formation of diverse secondary metabolites, such as shikimic acid, gallic acid pyrogallol, chlorogenic acid, and catechol [57]. For example, shikimic acid is an intermediate compound of this pathway. It has a highly functionalized, six-carbon ring with three chiral carbons and a carboxylic acid functional group. Therefore, it is widely used to synthesize valuable products such as the antiviral drug oseltamivir (Tamiflu®) [58].

2.2. Malonic Acid Pathway

Most of the phenolic compounds in higher plants are produced by the shikimate pathway, whereas in bacteria and fungi, the phenolic compounds are also synthesized by the malonic acid pathway [59].
The key enzyme tyrosine ammonia lyase deaminates tyrosine into p-coumaric acid in the malonic acid pathway. It is functionalized into p-coumaroyl-CoA by 4-coumaroyl CoA ligase. Then it reacts with three molecules of malonyl-CoA to give chalcone by chalcone synthase. The obtained tetraoxychalcone is transformed into flavanone–naringenin, which serves as a precursor to other flavonoids [60].

2.3. Mevalonic Acid Pathway (MVA)

The MVA pathway is present in most eukaryotes, archaea, and some bacteria. This pathway begins with the condensation of two acetyl-CoA molecules. It ends with the formation of isopentenyl-pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), the precursors to terpenoid biosynthesis [61].
In the MVA pathway, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) is produced from the sequential condensation of three molecules of acetyl-CoA catalyzed by acetoacetyl-CoA thiolase, and HMG-CoA synthase HMG-CoA is then converted to mevalonic acid by HMG-CoA reductase (HMGCR). Mevalonic acid is sequentially phosphorylated to 5-phosphomevalonate and 5-diphosphomevalonate and decarboxylated to generate IPP by the enzymes mevalonate kinase, 5-phosphomevalonate kinase, and 5-diphosphomevalonate decarboxylase. Finally, DMAPP is produced from IPP by a reversible reaction catalyzed by IPP/DMAPP isomerase [62].
HMGCR is the rate-limiting enzyme in the MVA pathway. There are two classes of HMGCR. Class I includes proteins of eukaryotic origin that are associated with the endoplasmic reticulum and are potentially inhibited by statins. Class II proteins of bacterial origin have low homology with class I HMGCRs (<20%). However, there is considerable similarity between the active sites of both classes of enzymes [63].

2.4. Methylerythritol-Phosphate (MEP) Pathway

The MEP pathway is an alternative route to MVA to produce terpenoid precursors (IPP and DMAPP). Most bacteria, cyanobacteria, and green algae exclusively use the MEP pathway. At the same time, plastid-bearing organisms have both pathways compartmentalized in the cytosol (MVA) and plastids (MEP) [64].
The MEP pathway initiates with the condensation between D-glyceraldehyde 3-phosphate and pyruvate to produce 1-deoxy-D-xylulose 5-phosphate (DXP), catalyzed by DXP synthase. DXP is then reductively isomerized to methylerythritol phosphate (MEP) by DXP reductoisomerase. Coupling between MEP and CTP is catalyzed by CDP-ME synthetase to produce methylerythritol cytidyl diphosphate (CDP-ME). CDP-ME is then phosphorylated to 4-diphosphocytidyl-2-C-methyl-D-erythritol-2-phosphate (CDP-MEP). CDP-MEP is cyclized to 2-C-methyl-D-erythritol-2,4-cyclodiphosphate (MEcPP). The opening of the cyclic pyrophosphate and the C3-reductive dehydration of MEcPP is catalyzed by 2-C-methyl-D-erythritol-2,4-cyclodiphosphate reductase to yield 4-hydroxy-3-methyl-butenyl 1-diphosphate (HMBPP). Finally, HMBPP is reduced to IPP and DMAPP by 4-hydroxyl-3-methyl-butenyl 1-diphosphate reductase [65].
Finally, it should be emphasized that although common molecular patterns and principles underlie life’s diverse forms, many differences in primary biosynthetic pathways exist. Many biosynthetic pathways are specific to certain groups of organisms. For instance, pheammonium lyase is a ubiquitous enzyme in fungi that catalyzes the deamination of L-Phe to trans-cinnamic acid. Conversely, only a few cinnamic and benzoic acid-derived metabolites have been described in prokaryotes [66].
From a practical perspective, the choice between using fungi or bacteria depends on the specific metabolite to be produced. Particular fungal or bacterial species exclusively synthesize some metabolites. Vancomycin, a glycopeptide antibiotic class, is produced by Amycolatopsis (formerly Streptomyces) species, such as A. orientalis or A. keratiniphila [67,68]. Although vancomycin is effective against methicillin-resistant Staphylococcus aureus infections [68], the emergence of vancomycin-resistant S. aureus has prompted the development of second-generation glycopeptide antibiotics. An example is the recently FDA-approved compound oritavancin. Although semi-synthetic, its production still relies on the in vivo production of vancomycin by Amycolatopsis species, and then the chassis is modified by incorporating a 4-(4-chlorophenyl) benzyl group through reductive alkylation [68].
Similarly, some secondary metabolites are exclusively synthesized by fungi. Beauvericin belongs to the cyclic hexadepsipeptide family and is produced via a non-ribosomal pathway utilizing beauvericin synthetase. It sequentially binds hydroxy isovaleric acid and N-methyl-phenylalanine molecules [69]. Certain entomopathogenic fungi generate Beauvericin, which exhibits diverse biological activities, including insecticidal, antimicrobial, and antitumor properties. Due to the intricate nature of its chemical synthesis, beauvericin production is predominantly accomplished via in vivo biosynthesis using specialized producer strains. Recently, Vásquez-Bonilla et al. [69] reported an enhancement in beauvericin production using solid-state cultures of Fusarium oxysporum AB2 compared to liquid cultures, increasing the yield from 0.8 mg/L to 65.3 mg/L. Moreover, they further improved yields by employing mixed cultures of F. oxysporum AB2 and Epicoccum nigrum TORT, producing 84.6 mg/L.

3. Using Precursors to Enhance Secondary Metabolite Production

Microbial metabolism is a valuable source of high-value compounds. Nevertheless, their industrial application could be limited since they are obtained in low concentrations [70]. Therefore, improving precursor supply and other strategies have been adopted to increase the production of these molecules [71], in addition to classical and molecular techniques for strain enhancement.
SSF has been recognized as better suited for the microbial mycelial morphology for secondary metabolite production [72]. SSF enabled the production of secondary metabolites with mosquitocidal activity [73], the plant hormone jasmonic acid [74], and bioactive compounds with growth-inhibition capacity against plant and human pathogenic bacteria [75]. Optimization of the culture conditions, including inoculation amount, fermentation time, temperature, pH, and others, is essential to maximize the yield and diversity of valuable compounds produced [76]. However, the production of some secondary metabolites in SSF remains challenging due to the low or unstable production yields that can be obtained. Such problems could be caused by limiting concentrations or even the absence of the endogenous precursors needed for the biosynthesis of the desired metabolites. Therefore, one approach to improve production yields is supplementing the culture media with these building blocks [10].
Exogenous precursors have been added to produce polyketides, a diverse class of natural products that have attracted significant attention due to their therapeutic potential [77]. These compounds are synthesized by enzymatic assembly of different building blocks, such as acetate and propionate, with the precursors to these reactions deriving directly or indirectly from primary metabolism. However, primary metabolism diminishes at the stationary growth phase, limiting polyketide production [77]. This limitation forms the basis for the exogenous supplementation of precursors, wherein these molecules can be added at the initiation of the culture or at specific time points to circumvent the scarcity of precursors during secondary metabolite production.
The production of lovastatin, a polyketide used as an anticholesterolemic drug, is an example of a secondary metabolism that can be improved by adding exogenous precursors. Rollini and Manzoni [78] showed that adding methionine to the culture media of four different Aspergillus terreus strains favored lovastatin biosynthesis in submerged fermentation. This work added methionine after 72 h of incubation, acting as the lovastatin precursor during the idiophase. Later, it was reported that methionine supplementation could also increase lovastatin production in SSF. Ábrego-García et al. [79] reported a lovastatin production of 23.8 mg/g dry matter fed in solid-state cultures of Aspergillus terreus CDBB H-194 growing in oat straw moistened with a liquid medium supplemented with methionine. The mechanism for this improvement could be explained by analyzing the biogenesis of statins in Aspergillus terreus. The biosynthetic pathway starts from acetate units (4 and 8 carbons long) linked to each other in a head-to-tail fashion to form two polyketide chains; the methylic group present in some statins in the side chain or at C6 derives from methionine and is inserted into the structure before the closure of the ring. Since lovastatin is a type of statin, the improvement of lovastatin production by the addition of methionine suggests that this compound works as a source of methylic groups during the synthesis of its polyketide chains [78].
In addition to polyketides, precursors have been used to enhance the production of other secondary metabolites. For instance, Rentería-Martínez et al. [80] found that the production of isoamyl acetate, a food additive with a banana-like odor, was around 30 times higher when adding isoamyl alcohol as the biosynthetic precursor than without the precursor addition. It was observed in submerged cultures of Pichia fermentans. This behavior was further observed in SSF, where the gradual supply of isoamyl alcohol to solid-state cultures of Pichia fermentans maintained a low yeast exposure to the precursor, avoiding or minimizing precursor toxicity [10]. It increased the production of isoamyl acetate more than 12-fold compared to the basal yield obtained without adding the precursor. In this case, isoamyl acetate was synthesized from the microbial esterification of isoamyl alcohol and acetyl-CoA in a reaction catalyzed by alcohol acetyltransferases I and II. Therefore, isoamyl alcohol acted as a direct precursor to the synthesis of isoamyl acetate [80].
In addition to improving production yields, culture supplementation with precursors can promote diversification of the secondary metabolites produced. In this regard, the one strain many compounds (OSMAC) approach has been shown to be a powerful tool to activate silenced gene clusters, producing multiple metabolites with diverse chemical structures and bioactivity. This methodology is based on the variation of culture conditions, genetic manipulation, and the feeding of biosynthetic precursors, which has proven useful in unlocking the biosynthetic potential of different microorganisms and, therefore, discovering new molecules [4].
Mantle et al. [81] studied a solid-substrate fermentation protocol for enabling secondary metabolite revelation of new idiolytes in Aspergillus ochraceus, a fungus known for producing ochratoxin A. After three days of SSF on shredded wheat breakfast cereal, different 14C-labelled biosynthetic precursors were added to cultures, including phenylalanine, acetic acid, and methionine. Through this experimental design, it was discovered that the fungus exhibited a capacity to diversify its metabolism and produce a broader range of extrolites in addition to ochratoxin A. Among them, notoamide R was identified. The key distinction between the synthesis of ochratoxins and notoamides concerns access to the branched primary metabolic pathway to aromatic amino acids for the end products phenylalanine and tryptophan. A reversibility of the action of any enzyme in the phenylalanine branch might point to variable secondary metabolism by redirecting that pathway to notoamides. This finding is significant in pharmaceutical development, as notoamides have shown interesting potential concerning L-DOPA deficiency associated with Parkinson’s disease [81].
As mentioned, metabolites like notoamide R were discovered and produced using wild-type strains. However, there are now several alternative methods that can also serve this purpose. These methods include heterologous expression of target genes, protein engineering, combinatorial biosynthesis, rewiring of biosynthetic pathways, and precursor-directed biosynthesis, among others [82,83]. For instance, the biosynthesis of polyketides has been attempted in heterologous hosts through the development of heterologous expression systems for polyketide synthases. However, this approach necessitates the functional expression of large multienzyme assemblies, the adequate fulfillment of their posttranslational modifications, and, most importantly, the availability of their substrates in vivo in the required quantities. Therefore, inserting genes that encode specific enzymatic activities, such as polyketide synthases, does not guarantee high production levels of the desired metabolites. It is essential to ensure the presence of the necessary intracellular precursors, such as acetyl-CoA, propionyl-CoA, malonyl-CoA, and methyl malonyl-CoA, among others [84].
An alternative approach to ensuring the availability of biosynthetic precursors involves the utilization of optimized strains, for example, industrial strains, that exhibit high-level production of secondary metabolites. Theoretically, these strains are more capable of providing sufficient biosynthetic precursors than wild-type microorganisms. Li et al. [82] investigated the utilization of Streptomyces cinnamonensis C730.7 for producing a heterologous polyketide product by introducing the entire tetracenomycin biosynthetic pathway using an integrative plasmid. S. cinnamonensis C730.7 is an industrial monensin producer strain that possesses a type I polyketide synthase responsible for monensin production from a combination of polyketide precursors, including malonyl-CoA, methylmalonyl-CoA, and ethyl malonyl-CoA. The study successfully produced 0.6 g/L of tetracenomycin C and 4.35 g/L of tetracenomycin A2 without reducing monensin production. Interestingly, since both tetracenomycin and monensin are synthesized from malonyl-CoA as a precursor, these results indicate that in the case of this strain, tetracenomycin production does not compete with monensin production for malonyl-CoA utilization and that this strain can provide sufficient biosynthetic precursors for both biosynthetic pathways. In contrast, in a non-industrial strain of S. cinnamonensis, the utilization of malonyl-CoA for tetracenomycin synthesis negatively impacted monensin production. These findings highlight the variability in polyketide metabolism observed across different strains and explain the current focus of synthetic biology on understanding and optimizing metabolic pathways for endogenous precursor supply.
Regarding the enhancement of the endogenous supply of biosynthetic precursors, Leonard et al. [83] studied the effect of amplifying the flux towards the synthesis of the precursors (isopentenyl diphosphate and dimethylallyl diphosphate) from the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway on levopimaradiene production in Escherichia coli. This was achieved by incrementally overexpressing the bottleneck enzymatic steps in the MEP pathway. The strategy resulted in improved production of levopimaradiene. Additionally, to accommodate the increased precursor supply, the authors explored the molecular reprogramming of key metabolic nodes, including prenyl transferase (GGPPS) and terpenoid synthase (LPS), through protein engineering. This combination of metabolic and protein engineering methods increased levopimaradiene production, leading to a remarkable 2600-fold increase in levopimaradiene levels. Similarly, Hao et al. [85] enhanced the production of avermectin B1a in the high-yield industrial strain Streptomyces avermitilis A229 by engineering precursor supply genes and the aveC gene, which is implied in determining the ratio of avermectin 1 to 2 components. This combined strategy led to a maximum avermectin B1a titer of 9613 μg/mL, representing a significant 49.1% increase compared to the unmodified strain.

4. Enhancing Secondary Metabolite Production in SSF

4.1. Stimulating Internal Precursor Generation

Some works have exploited internal precursor generation to increase product synthesis. Hao et al. [86] used a two-step supply strategy to enhance the production of tetramethylpyrazine, a flavoring additive with a nutty and roasted taste, by Bacillus subtilis in SSF. They added 10% glucose at the beginning of fermentation, stimulating the accumulation of acetoin, the tetramethylpyrazine precursor. Later, when acetoin accumulation was at maximum, 3% diammonium phosphate was added to increase the acetoin accumulation 2.4-fold. This led to a 6.8-fold increase in tetramethylpyrazine production. Later, Zhang et al. [87] enhanced tetramethylpyrazine production in SSF by using a mix composed of wheat bran (50.8%), soybean meal (21.8%), distillers’ grains (a by-product of the Chinese liquor industry, 26.6%), and NaOH (0.8%). The authors of this research found that the addition of distillers’ grains improved tetramethylpyrazine production. They argued that the solid media composition allowed acetoin production to be increased during the first two days of incubation. Then, the acetoin content of the media diminished, and tetramethylpyrazine accumulation reached its highest concentration at 3.5 days.
Kosakonia cowanii produced an exopolysaccharide that promotes plant growth activity [88]. The bacterium produced a maximum exopolysaccharide yield in SSF using a mixture of cane bagasse and broad bean seed capsules (2:1) supplemented with 5% cane molasses powder and 4.16% NaNO3. The authors performed a transcriptomic analysis, finding that NaNO3 induced the upregulation of eight nucleotide–sugar biosynthesis genes. They argued that it increased energy supply and metabolites such as UDP-glucose, UDP-glucosamine, and GDP-fucose, precursors to exopolysaccharide biosynthesis. Finally, the authors indicated that NaNO3 increased the expression levels of exopolysaccharide synthases and proteins for exopolysaccharide biosynthesis.

4.2. Using Precursors That Are Already Content in the Solid Material

Precursors may already be present in SSF substrates to produce secondary metabolites. This is the case for ferulic acid, used as a precursor to vanillin production. High vanillin production has been reported in SSF using wheat straw [39] and sugarcane bagasse [37] due to their high ferulic acid content, which is used as a precursor.
Lindsay et al. [89] tried identifying natural flavor and aroma metabolite sources, testing nine agro-industrial by-products in SSF. The authors used four filamentous fungi and reported vanillin production by Penicillium camemberti when fermenting olive cake. They highlighted that there are no reports on the capacity of P. camemberti to produce vanillin. Therefore, the fungus must biotransform some precursors present in the olive cake, which is rich in lignin, polyphenols, and phenolic acids [90].
On the other hand, glutamate is used as a precursor to produce γ-aminobutyric acid, which is dispensed to treat some neuronal disorders and is gaining relevance in the field of functional foods [91,92,93,94]. Cai et al. [95] reported that oat grains fermented by Aspergillus oryzae to produce a tempeh-like food showed a γ-aminobutyric acid content 8-fold higher than raw material. The authors attributed the increase to the high glutamate decarboxylase activity of A. oryzae to convert glutamate into γ-aminobutyric acid.
Khan et al. [96] reported producing Monascus-fermented rice with a high content of GABA but a low amount of citrinin. This secondary metabolite is neurotoxic to humans. The authors first tested six solid substrates (barley (Hordeum vulgare), cassava (Manihot esculenta Crantz), jowar (Sorghum bicolour), oat (Avena sativa), rice (Oryza sativa), and sweet potato (Ipomoea batatas)). Rice had the best γ-aminobutyric acid production because of its high content of the precursor glutamic acid. Subsequently, seven Monascus species were tested for γ-aminobutyric acid production by SSF of rice, with one strain with the highest γ-aminobutyric acid production being identified. They explained the differences in γ-aminobutyric acid production capacity by the differences in the expression level of the glutamate decarboxylase enzyme among the Monascus species. Monascus-fermented rice production was optimized for maximum γ-aminobutyric acid and minimum citrinin production using a Box–Behnken design followed by response surface methodology. The authors concluded that rice supplemented with lactose, alanine, malt extract, and ZnSO4 enhanced γ-aminobutyric acid production (25-fold concerning control SSF) and reduced citrinin generation.
Solid-state fermentation with Poria cocos, an edible and medicinal fungus, led to a 5.16-fold increase in the content of astragaloside IV in the dried root of Astragalus membranaceus (Radix Astragali) [97]. Astragaloside IV is a triterpenoid saponin recognized as a quality marker for Radix Astragali, which is used as a health additive in foods and beverages. Anti-inflammatory, anti-fibrotic, anti-oxidative stress, anti-asthma, anti-diabetes, immunoregulation, and cardioprotective effects are some of the healthy effects attributed to astragaloside IV [98]. Chen et al. [97] argued that other astragalosides could be precursors during SSF to obtain astragaloside IV.

4.3. Adding External Precursors to SSF

Precursors can be added to the solid substrate to enhance the production of the desired compound. The fungus Monascus sanguineus produced γ-aminobutyric acid using coconut oil cake as the substrate for SSF [99]. A Plackett–Burman design allowed the authors to identify monosodium glutamate as the precursor, pH, and incubation time as the significant variables for γ-aminobutyric acid production. Then, γ-aminobutyric acid production was optimized by response surface methodology, and it was found that the maximum yield was obtained with a monosodium glutamate concentration of 0.05 g per gram of dry coconut oil cake incubated at pH 7.5 for 20 days. The authors identified glutamate addition as the major factor influencing γ-aminobutyric acid production.
Kluyveromyces marxianus produced γ-aminobutyric acid in SSF by adding L-glutamate or monosodium glutamate to okara, a by-product obtained during soybean use to make products like soymilk and tofu [100]. This work performed a single-factor experiment to identify the process factors influencing γ-aminobutyric acid production, followed by response surface methodology based on the Box–Behnken center combination design. This led to the finding that K. marxianus efficiently converts both L-glutamate and monosodium glutamate into γ-aminobutyric acid, with maximum production obtained at 35 °C, pH 4.0, and 60 h of incubation.
Apple pomace was identified as an agro-industrial waste that could produce 2-phenyl ethanol in SSF. Moreover, the final concentration and productivity increased by 15 and 17.5%, respectively, by adding L-phenylalanine as a precursor [101]. This work concluded that reducing the sugar content of the substrate, the air-filled porosity of the solid bed, and the L-phenylalanine availability significantly influenced aroma production. Roy et al. [102] reported 30–75% increases in the 2-phenyl ethanol and 2-phenyl acetate production in SSF due to the addition of L-phenylalanine. They concluded that Kluyveromyces marxianus could be a cell factory to produce these aroma compounds by adding synthetic L-phenylalanine.
Supplementation of a mix of three Chinese medicines to SSF cultures permitted an enhanced production of monakoline K by Monascus ruber [103]. These researchers also found six genes of M. ruber involved in monakoline K production. Finally, they proposed that the expression of those genes was modulated by key components in Chinese medicines, which remain unidentified.
Bacillus amyloliquefaciens produced γ-polyglutamic acid in SSF using a mix of corn stalk and soybean meal as solid substrates and industrial monosodium glutamate as the precursor [104]. Response surface methodology allowed for an optimized composition of corn stalk, soybean meal, and industrial monosodium glutamate (5/5/1, v/v/v). Fang et al. [104] observed simultaneous industrial monosodium glutamate and γ-polyglutamic acid production, confirming the role of the former as a precursor to synthetizing the product. They reported that the bacterium biotransformed nearly 90% of the industrial monosodium glutamate supplied to the γ-polyglutamic acid.
Recently, isoamyl acetate (banana-like aroma) production was enhanced by supplying the precursor, isoamyl alcohol, through the airstream used normally in SSF to provide oxygen to the culture [10]. Polyurethane foam served as an inert support for growth of the yeast Pichia fermentans using a simple medium of cane molasses (10% w/v) at pH 5.0. The work proved the feasibility of supplying volatile molecules other than oxygen using an airstream and a bubbling column. Moreover, it was also proven that the addition rate can be modulated by changing the airflow rate and the concentration of the volatile molecule in the bubble column. Isoamyl alcohol is toxic to yeasts. Thus, the authors used the gas phase to gradually feed the precursor, trying to avoid or minimize toxicity to the precursor. This strategy increased the isoamyl acetate production 12.5 times compared to production without a precursor supply.

5. Discussion

As shown in Figure 2, three main ways to use precursors for secondary metabolite production by microorganisms can be identified. Medium composition and fermentation conditions are modified to stimulate the generation of metabolites that serve as precursors. Changing medium components or their concentrations could affect the carbon flux distribution in the metabolism, leading to precursor accumulation, as reported previously [86,87], for acetoin accumulation during tetramethylpyrazine production. Other studies reported transcriptomic changes because of modifications in the culture medium composition. this means that transcriptomic adjustments (activating silenced gene clusters, gene upregulation, and gene downregulation) promote the diversification of secondary metabolite production. This is the case reported by Gao et al. [88], who found transcriptomic changes during exopolysaccharide production when supplementing cane molasses powder and NaNO3. They claimed transcriptomic changes increased energy supply and precursor biosynthesis for exopolysaccharide production.
A second way to use precursors is to achieve molecules already in the solid substrate. This depends on certain factors, such as the enzymatic capacity of the microorganism to convert the precursors, the content of the precursor in the substrate, and the bioavailability of the precursor. The most common is identifying substrates rich in a molecule that can be used as a precursor and combining them with microorganisms with a high capacity to biotransform the molecule. The production of biovanillin from agro-industrial residues such as wheat straw [39], sugarcane bagasse [37], and olive cake [90] was reported with this method. Similarly, γ-aminobutyric acid was produced from rice [96]. Finally, some processes try to increase a beneficial compound’s content, achieving the addition of the content of the precursor to the substrate. This was the case for the enrichment of tempeh-like food with γ-aminobutyric acid [95] culturing A. oryzae and the fortification of Radix Astragali with astragaloside IV [97].
Finally, the third way to use precursors is by supplying them to SSF. As mentioned in Figure 1, precursors can be added directly to the liquid phase, which is frequently a solution that complements the nutritional characteristics of the solid substrate. In the case of inert solid supports, the liquid phase is the culture medium. It was used to produce γ-aminobutyric acid biotransforming monosodium glutamate [99,100], or L-glutamate [100]. Similarly, L-phenylalanine was added as the precursor to produce 2-phenyl ethanol [101].
Conversely, it has been proposed recently [10] that an airstream used to supply oxygen can be achieved by adding volatile molecules as precursors for secondary metabolite production. In any case, when considering enhancing secondary metabolite production in solid-state fermentation through precursor addition, it is crucial to consider several factors influencing its success. These factors include the specific culture conditions, the microorganism utilized, and the added precursor’s type, stability, and potential toxicity. Additionally, the timing of precursor addition plays a crucial role in producing specific metabolites and may vary among different microorganisms.
Figure 3 shows two possible strategies for adding precursors to a solid-state bioreactor. Figure 3A depicts the case when the precursor is a non-volatile compound. The precursor can be added directly to the culture medium if it is a non-toxic or inhibitory molecule for the microorganism. Conversely, the precursor could be added using a pump and sprayed onto the solid material. If the microorganism is not damaged, the solid material should be mixed to homogenize it and achieve a better result.
Figure 3B illustrates the supply of a volatile molecule that enters the system through the bubbling column used to humidify the airstream that provides oxygen to the culture. In both cases, a control algorithm permits signals from sensors to be obtained and processed to control pumps and valves for precursor supply modulation.
The precursors are added to be transformed in a particular metabolic pathway. However, they can be substrates of enzymes that participate in more than one metabolic pathway or be converted by enzymes of low specificity. This can cause at least part of the added precursor to be redirected to a part of the metabolism other than the intended one. The precursor or one of its derivatives must react with some key metabolites, such as acetyl-CoA or pyruvate, used in various metabolic pathways. This type of situation can cause low efficiency in using the added precursor.
Biological or physical factors may limit bioreactor performance. Considering the bioconversion of exogenous precursors, enzyme activity and cell-membrane transport are the main biological factors influencing the bioreactor performance. Conversely, the adequate supply of the precursor to the cell depends on the physical proper functioning of the bioreactor.
Exogenous precursors are molecules that break into the metabolism of a functional cell and must be assimilated by the appropriate metabolic pathway. Likewise, it is known that enzyme activity depends on substrate concentration, among other factors. Then, precursor supply allows for increased substrate availability, which could increase the corresponding pathway’s metabolic flux, resulting in increased product formation. Nevertheless, the precursor addition effectivity of enhancing product formation is subjected to constraints. The greater substrate availability increases the possibility of a substrate–enzyme face improving the enzyme reaction rate. Still, it cannot change the maximum enzyme reaction rate, an intrinsic system characteristic. Something similar has been argued by Oreb [105] for an artificial protein complex design to eliminate metabolic bottlenecks.
On the other hand, getting the precursor to the cell is the job of the bioreaction system used. A bioreactor is a physical place that provides the conditions for cell growth and metabolite production. An excellent review of the general types of SSF bioreactors was provided by Ge et al. [106]. They describe the design, heat, and mass transfer for tray, packed-bed, rotating-drum, stirred-drum, fluidized-bed, rocking-drum, and stirred-aerated bioreactors. Complementary to this, Chen [107] reviewed significant biological and engineering aspects of SSF, such as water evaporation, heat transfer in porous media, the moisture relevance, evaporation heat removal, particle size and shape, and changes in solid material properties caused by microbial growth, among others. Chen [107] and Ge et al. [106] agree that scaling up is the biggest challenge or bottleneck for the industrial application of SSF. Ge et al. [106] identified heat transfer as the main problem. They argued that the reason is the solid material’s poor thermal conductivity and heat capacity compared to a liquid medium. Chen [107] considered that heat, mass transfer, and aseptic operation are the main factors affecting the scaling up of SSF bioreactors.
If a precursor solution is sprayed on a culture of a filamentous fungus that suffers damage if the solid material is mixed, a tray bioreactor with thin beds of solid material may be a good choice. Still, in a similar case growing yeast, a stirred-drum bioreactor seems to be a better option since it allows for enhanced heat and mass transfer, benefiting the medium homogeneity and bioconversion yield. In contrast, a packed-bed bioreactor is the best option for a volatile precursor added using the airstream to provide oxygen. However, the homogeneous distribution of the precursor can be complex due to the formation of preferential flow channels, which occur primarily when filamentous fungi are cultivated. Thus, it is clear that the appropriate selection of bioreactor design to produce secondary metabolites successfully depends on a careful and in-depth analysis of each particular system.

6. Concluding Remarks and Future Directions

Although rewiring biosynthetic pathways has shown promise as a strategy to enhance the production of various secondary metabolites, this technique is still in its early stages of development. Furthermore, most studies on rewiring pathways have focused on submerged cultures, and there needs to be more research on utilizing these modified strains in SSF. Therefore, further investigation is needed to explore the potential of rewired strains in solid-state cultures and to assess their efficacy in secondary metabolite production under such conditions. In the meantime, supplementing cultures with exogenous precursors remains a viable approach.
It has been considered that precursor supply strategies are challenging to apply to SSF systems [108]. Future work on the rational development of strategies to supply precursors must consider engineering criteria to produce compounds of biotechnological interest. The basis must be a thorough knowledge of the precursors’ physical, chemical, and biological properties and the system they will interact with (solid support + culture medium). Appropriate selection of the type of bioreactor is also a transcendental factor to reach a high precursor bioconversion. This will allow for the design of strategies and control systems to regulate the precursor addition. Likewise, mathematical models will be required to describe the behavior of fermentation systems and serve as a basis for implementing control algorithms. Finally, more rapid progress must be made in scaling up SSF bioreactors to achieve significant participation of this technology in the commercial production of microbial secondary metabolites.

Author Contributions

Conceptualization, N.O.S.-C.; writing—original draft: J.E.M.-H., L.V.R.-D., J.B.P.-L. and N.O.S.-C.; writing—review and editing: J.E.M.-H., L.V.R.-D., J.B.P.-L. and N.O.S.-C. All authors have read and agreed to the published version of the manuscript.

Funding

This work received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Schematic diagram of the main metabolic pathways involved in the production of secondary metabolites by microorganisms.
Figure 1. Schematic diagram of the main metabolic pathways involved in the production of secondary metabolites by microorganisms.
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Figure 2. Overview of the strategies for using precursors.
Figure 2. Overview of the strategies for using precursors.
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Figure 3. Strategies for supplying precursors to a solid-state bioreactor by direct liquid addition (A) and using the airstream to provide oxygen (B).
Figure 3. Strategies for supplying precursors to a solid-state bioreactor by direct liquid addition (A) and using the airstream to provide oxygen (B).
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Table 1. Examples of secondary metabolites produced by SSF.
Table 1. Examples of secondary metabolites produced by SSF.
Metabolite and Its Potential ApplicationMicroorganismSolid SupportYield (mg/g SS)Reference
Pigments
Monascin, ankaflavin, rubropunctatin, monascorubrin, rubropunctamin, monascorubramine, etc.Monascus sp.Rice49.65 *[12,13]
Antibiotics
PenicillinPenicillium chrysogenumSugarcane bagasse7–8[14,15]
Cephalosporin CAcremonium chrysogenumSugarcane bagasse3.2[16,17]
ParomomycinStreptomyces rimosusCorn bran2.2[18]
NeomycinStreptomyces fradiaeNylon spongen.d.[19]
Rifamycin BNocardia mediterraneiSunflower oil cake9.87[20]
Antifungal
SclerotiorinPenicillium sclerotiorumRicen.d.[21]
GriseofulvinPenicillium griseofulvumRice bran9–10[22]
NatamycinStreptomyces gilvosporeusWheat bran, rapeseed cake, and rice hull9.62[23]
Statins
LovastatinAspergillus terreusGlucose and lactose19.95–25[24,25,26]
Compactin (mevastatin)Penicillium brevicompactumSoybean meal1.406[27]
Monacolin KMonascus ruberMillet19.81[28]
Rice and bran14.53[29]
Biosurfactants
SurfactinBacillus subtilisOlive cake flour30.67[30]
Bacillus amyloliquefaciensSoybean flour15.03[31]
IturinBacillus subtilisDefatted soybean meal, wheat bran and ricehusk5.58[32]
RhamnolipidsPseudomonas aeruginosaPolyurethane foam39.8 **[33]
Soybean meal19.68[34]
SophorolipidsStarmerella bombicolaPolyurethane foam211 ***[35]
Wheat straw195[36]
Phenolics
VainillinEnterobacter hormaecheiSugarcane bagasse4.76[37]
Enterobacter hormaecheiPomegranate peels0.462[38]
Streptomyces sannanensisWheat straw2.74[39]
Gallic acidAspergillus nigerBlack plum seed14.5[40]
HispidinPhellinus linteusBrown rice and pearl barley0.375[41]
Immunosuppressants
Mycophenolic acidPenicillium brevicompactumParmal rice4.5[42]
Cyclosporin ATolypocladium inflatumWheat bran flour and coconut oil cake6.48[43]
Phytohormones
Gibberellic acidGibberella fujikuroiAmberlite IRA-900n.d.[44]
Alkaloids
ErgotamineClaviceps purpureaRice≈0.015[45]
* Optical density unit (ODU)/g SS, ** g/L, *** mg/g substrate, n.d. = not determined.
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Méndez-Hernández, J.E.; Rodríguez-Durán, L.V.; Páez-Lerma, J.B.; Soto-Cruz, N.O. Strategies for Supplying Precursors to Enhance the Production of Secondary Metabolites in Solid-State Fermentation. Fermentation 2023, 9, 804. https://doi.org/10.3390/fermentation9090804

AMA Style

Méndez-Hernández JE, Rodríguez-Durán LV, Páez-Lerma JB, Soto-Cruz NO. Strategies for Supplying Precursors to Enhance the Production of Secondary Metabolites in Solid-State Fermentation. Fermentation. 2023; 9(9):804. https://doi.org/10.3390/fermentation9090804

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Méndez-Hernández, Jazmín E., Luis V. Rodríguez-Durán, Jesús B. Páez-Lerma, and Nicolás O. Soto-Cruz. 2023. "Strategies for Supplying Precursors to Enhance the Production of Secondary Metabolites in Solid-State Fermentation" Fermentation 9, no. 9: 804. https://doi.org/10.3390/fermentation9090804

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