ABSTRACT
Keywords: Secondary Metabolism, Streptomyces, Immunologic Factors, Anti-infective Agents.
RESUMO
Palavras-chave: Metabolismo Secundário, Streptomyces, Fatores Imunológicos, Anti-Infecciosos.
RESUMEN
Palabras clave: Tratamiento Secundario, Streptomyces, Factores Inmunológicos, Antiinfecciosos.
1 INTRODUCTION
The genus Streptomyces comprises gram-positive bacteria belonging to the phylum Actinobacteria, characterized by a high G+C content in their DNA, ranging from 50% to 70%. Morphologically, these microorganisms are spore-forming and produce hyphae that develop into an aerial mycelium, resulting in filamentous growth. This structure enhances their resistance and survival in various habitats, including terrestrial and marine environments (Kronheim et al., 2023; Luthe et al., 2023).
These bacteria are recognized for their prolific production of bioactive compounds derived from their secondary metabolism through the production of enzymatic systems and synthesis of substances, making them a group of high clinical and biotechnological relevance. They exhibit antioxidant, antiparasitic, anticancer, immunosuppressive, and antimicrobial activities (Ab Mutalib et al., 2020; Santos et al., 2024). Currently, they are responsible for the production of two-thirds of the antibiotics available on the market, with approximately 80% derived from the genus Streptomyces. Notable antibiotics of significant clinical and therapeutic importance include streptomycin, erythromycin, and tetracycline (Amorim et al., 2020; Lin et al., 2022).
Despite the variety of compounds already isolated, the emergence of multidrug-resistant microorganisms has increased dramatically. These pathogens seek mechanisms to evade and block the immune response. Once reaching their target, these microorganisms proliferate in the host, leading to infection and exhaustion. Included in this group of microorganisms are Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Neisseria gonorrhoeae, Streptococcus pneumoniae, Mycobacterium tuberculosis, among others (Alam et al., 2022; Pinto et al., 2021).
The immune system is responsible for defending and protecting the organism against agents recognized as foreign. After detection, it signals and recruits cells to achieve homeostasis and integrity (Ghosh et al., 2020). Immunomodulatory agents can assist the immune system by altering its function, potentially acting as immunostimulants or immunosuppressants (Targino et al., 2022; Zhao et al., 2020). Therefore, the search for biomolecules that beneficially modulate the immune system is crucial. The genus Streptomyces is a promising candidate due to its secretion of a variety of structurally diverse products.
Thus, this study aims to conduct a literature review on the use of secondary metabolites from Streptomyces sp. as immunomodulatory agents.
2 STREPTOMYCES: GENERAL CHARACTERISTICS
Actinobacteria (phylum Actinomycetota) represent gram-positive, filamentous, spore-forming bacteria that produce secondary metabolites. These compounds provide advantages in growth, reproduction, and the perpetuation of the microorganism, especially in environments where there is ecological competition for nutrients and territory among various species (Quinn et al., 2020). These metabolites are notably recognized for their significant antimicrobial activity, with great utility in clinical, pharmaceutical, and industrial contexts (Sivalingam et al., 2019).
Among all actinomycete genera, species of Streptomyces are particularly prominent for their metabolism of antimicrobial compounds, producing approximately 100,000 substances with some antibiotic activity, which represent about 70-80% of all bioactive natural products with pharmacological or agrochemical applications. Streptomyces constitutes about 95% of all actinomycete species present in terrestrial soil (Barka et al., 2016; Alam et al., 2022).
Decades after their discovery, metabolites from Streptomyces continue to be explored by researchers, who employ a range of strategies to stimulate the production of new metabolites by these species, including modification of culture conditions and genetic techniques such as heterologous expression and genomic mining (Lacey; Rutledge, 2022). The genome of Streptomyces spp. contains various regions known as biosynthetic gene clusters (BCGs), responsible for encoding multienzymatic complexes that act in the synthesis of bioactive metabolites (Lee et al., 2020).
The nomenclature Streptomyces was first proposed by Waksman and Henrici (1943) when they isolated a new aerobic, saprophytic, spore-forming actinomycete from soil. Since then, hundreds of species within this genus have been isolated from various habitats, including soil, terrestrial and marine sediments, and extreme environments. These bacteria are also capable of colonizing symbiotically other organisms, such as plants, fungi, and animals (Law et al., 2019). Currently, more than 800 Streptomyces strains have been registered and validated, consolidating Streptomyces as the largest genus of secondary metabolite producers (Donald et al., 2022).
Actinomycetes also exhibit significant biochemical properties, including the production of enzymes that degrade high-complexity macromolecules, such as lipases, proteases, and cellulases. These enzymes also show excellent stability under temperature and pH variations, making them widely used in industrial applications (Moreira; Siqueira, 2006). Their presence is also crucial in soil biodegradation processes, as well as in the formation of humus and the production of volatile substances like geosmin, which is responsible for the characteristic "wet earth" odor of these microorganisms (Alam et al., 2022).
In this context, actinomycetes represent an extensive and diverse phylum of bacteria with a global distribution, notable for their production of secondary metabolites with biological activity. Bioactive substances derived from Streptomyces have the capability to act as antimicrobial, antiviral, antioxidant, pesticide, herbicide, antitumor, and immunosuppressive agents (Alam et al., 2022). The metabolites of these microorganisms, such as antibiotics, lectins, and peptides, have been described as immunomodulators in various experimental models (Fateh et al., 2015).
3 ANTIMICROBIAL ACTIVITY
Streptomyces é um gênero de bactérias pertencentes à classe das actinobactérias, que têm grande importância para o setor biotecnológico, uma vez que são amplamente reconhecidas como grandes produtoras de moléculas bioativas derivadas do seu metabolismo secundário, com diversas atividades já relatadas, especialmente sua atividade antimicrobiana para uso clínico e agrícola (Barka et al., 2016; Saldaña et al., 2020; Santos et al., 2020; Rios-Hernández et al., 2021).
A busca por novas biomoléculas com potencial para inibição e/ou destruição de agentes infecciosos começou após o advento da penicilina em 1928 por Alexander Fleming, o que levou à descoberta de novos antibióticos através da bioprospecção de produtos naturais microbianos (Goredema et al., 2020). Por exemplo, em 1944, Waksman e Schstz isolaram a estreptomicina a partir de Streptomyces griseus, sendo o primeiro medicamento eficaz no tratamento da tuberculose e apresentando grande potencial contra Mycobacterium tuberculosis.
De acordo com Pšeničnik et al. (2022), mais de 10 mil compostos bioativos já foram obtidos de actinobactérias, dos quais aproximadamente 75% advêm do gênero Streptomyces. Atualmente, essas bactérias são responsáveis pela produção de aproximadamente 80% dos antibióticos disponíveis no mercado, com grande importância clínica. Entre esses antimicrobianos estão as classes dos aminoglicosídeos, macrolídeos, β-lactâmicos, peptídeos, polienos, entre outros (Tomaseto et al., 2020; Evangelista-Martínez et al., 2022). A Tabela 1 lista alguns dos antibióticos promissores oriundos de Streptomyces sp.
Apesar das descobertas e avanços relacionados a essas classes de medicamentos, as doenças infecciosas continuam a figurar entre as principais causas de morte em todo o mundo, afetando principalmente indivíduos imunossuprimidos, crianças e idosos. A resistência aos antimicrobianos está se tornando cada vez mais um problema de saúde pública, uma vez que os agentes infecciosos buscam mecanismos através da formação de estruturas, como biofilmes, que conferem ao microrganismo uma resistência ampla a diversas substâncias (Neamah et al., 2020).
Studies report the resistance of S. aureus to various antibiotics, such as aminoglycosides, glycopeptides, and some quinolones. The increasing resistance of this pathogen to vancomycin is particularly concerning, as it is currently the drug of choice for treatment. In 2017, the WHO published a list of 12 bacterial species considered a priority due to antibiotic resistance. Asokan et al. (2019) analyzed the major pathogens reported as resistant, with methicillin-resistant S. aureus (MRSA) being the most frequently reported, followed by Enterobacteriaceae resistant to extended-spectrum beta-lactamases (ESBL) and Enterococcus faecium resistant to vancomycin.
Another promising substance is platensimycin, isolated from S. platensis. Currently in preclinical studies, it shows significant promise against MRSA and vancomycin-resistant Enterococcus spp., acting on fatty acid biosynthesis and reducing pathogen resistance and toxicity (Cartuche Flores et al., 2021). Mu et al. (2020) conducted a study on actinomycin D isolated from Streptomyces luteus, demonstrating inhibition of biofilm formation by Staphylococcus epidermidis, making it a potentially valuable substance for reducing infections associated with this resistance structure.
The results and discussions of an article should be presented clearly and systematically, based on the data collected and analyses performed during the study. Initially, results should be presented objectively and concisely, using tables, graphs, and statistics if applicable, to highlight the main findings. Subsequently, in the discussion section, results are interpreted in light of existing literature, emphasizing similarities, differences, and implications for theory and practice.
Furthermore, the limitations of the study and possible directions for future research should be discussed. It is essential that both results and discussion are grounded in solid evidence and contribute significantly to advancing knowledge on the topic addressed.
4 IMMUNOMODULATION OF METABOLITES FROM STREPTOMYCES SP.
In addition to antimicrobial activity, several studies aim to highlight the immunomodulatory effects of secondary metabolites from Streptomyces spp., which regulate the immune response either positively or negatively during an aggressive stimulatory process. Below are some compounds derived from Streptomyces spp. that show promising results in immunomodulating various immunological processes (Table 2).
4.1 CYTOKINE MODULATION
Cytokines are soluble proteins of low molecular weight secreted by various cells, such as lymphocytes, macrophages, and natural killer cells, responsible for mediating and communicating all reactions seen in the immune response (Kulbe et al., 2012). They are classified into categories, including tumor necrosis factor (TNF-α), interleukins (ILs), lymphokines, monokines, interferons (IFNs), colony-stimulating factors (CSFs), and transforming growth factors (TGFs) (Sprague; Khalil, 2009). Depending on the stimulus, cytokines can be classified as pro-inflammatory (e.g., IL-1β, IL-6, IL-8, IL-12, TNF-α), which stimulate inflammatory reactions and immune-competent cells; or anti-inflammatory (e.g., IL-4, IL-6, IL-10, IL-11, IL-13, TGF-β), which mediate the immunosuppression of the inflammatory response (Boshtam et al., 2017; Liu et al., 2021). As regulators of the immune response, cytokines are the primary target for the development of immunotherapeutics based on natural compounds such as those derived from Streptomyces spp.
TNF-α is a master cytokine that regulates inflammatory response and innate immunity. The main pathways activated by this cytokine include caspases, nuclear factor-kappa B (NF-κB), and mitogen-activated protein kinases (MAPK). Its regulation is crucial to prevent an excessive inflammatory response (Wong et al., 2008; Tiegs; Horst, 2022). NF-κB and MAPK are the primary pathways of pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) (Shabab et al., 2017). The NF-κB pathway consists of five transcription factors (p50/p105, p52/p100, p65 (RelA), c-Rel, and RelB), which are dispersed in the cytoplasm bound to inhibitory molecules of the IκB type (IκBα, IκBs, IκBβ, IκBγ, and IκBε). During an aggressive process, the immune system releases cytokines such as TNF-α and IL-1, which induce the phosphorylation of the NF-κB/IκB complex. Free NF-κB translocates to the nucleus and binds to DNA at specific sequences to regulate the expression of target genes, including the regulation of immune and inflammatory responses, such as the expression of pro-inflammatory cytokines (e.g., IL-6, IL-1β, and TNF-α), production of reactive oxygen species (ROS), and cellular apoptosis (Jimi et al., 2005; Hayden et al., 2014; Jimi et al., 2019). The MAPK pathway includes extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, which are also activated by pro-inflammatory stimuli such as TNF-α production and cellular stress. MAPK shares a common structure composed of three sequential action proteins, including a MAPK kinase (MAPKK) and a MAPKK kinase (MAPKKK), along with some non-canonical exceptions (ERK3, ERK4, ERK7, and ERK8). This pathway mediates the activation of downstream substrate phosphorylation, including transcription factors, cytoskeletal proteins, mRNA translation, and other kinase proteins (Morrison; Davis, 2003; Kyriakis; Avruch, 2012; Sabio; Davis, 2015; Yang et al., 2020). The NF-κB and MAPK pathways have well-defined and elucidated mechanisms, making them the main targets for new therapeutic approaches, including immunomodulatory activity by Streptomyces spp. metabolites.
Anhydroesfoliamycin is a compound produced by Streptomyces spp. that can inhibit the activation of microglial cells in the pro-inflammatory M1 phenotype, which are responsible for the release of pro-inflammatory cytokines, including pro-inflammatory interleukins (IL) and TNF-α (Norden; Godbout, 2013; Tang; Le, 2016), as well as nitric oxide (NO) and ROS (Cherry et al., 2014). This pro-inflammatory activation, if exacerbated and chronic, can lead to neurodegenerative damage, such as Alzheimer's and Parkinson's diseases (Zusso et al., 2019). Anhydroesfoliamycin is identified as a potential neuroprotective agent against neurodegenerative diseases due to its modulation of the NF-κB and MAPK pathways, reducing the expression of pro-inflammatory cytokines and compounds (Alvarino et al., 2019; Gegunde et al., 2021).
A similar effect was observed with ebosine, a new exopolysaccharide (EPS) isolated from Streptomyces sp. 139. The metabolite was found to decrease the mRNA expression levels of genes encoding pro-inflammatory cytokines IL-23, IL-22, IL-17α, IL-6, IL-1β, and TNF-α, providing a mitigating effect on inflammatory activity at both transcriptional and post-transcriptional levels. Additionally, the compound inhibited the genes tnfaip3, tnip1, and IκBα, key genes that regulate the pro-inflammatory NF-κB signaling pathway, interrupting the binding of NF-κB and DNA, which leads to reduced cytokine expression. Ebosine also showed activity in the negative regulation of p38 MAPK and JNK phosphorylation induced by TNF-α (Zhang et al., 2013; Guo et al., 2021; Zhang et al., 2022).
The gene expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) was suppressed by the action of streptinone, a new indanone derivative from Streptomyces massiliensis of marine origin, resulting in reduced inflammatory activities caused by particulate matter. Additionally, the compounds were responsible for decreased phosphorylation and nuclear translocation of IκB-α, p65, and p50, suppressing pro-inflammatory pathways, such as NF-κB pathway mediated by TLR (Lee et al., 2023).
The marine isolate Streptomyces specialis 208DD-067 produces different compounds of the streptoglyceride family (A-H), with confirmed anti-inflammatory activity. The streptoglyceride compounds showed inhibitory effects on inflammatory mediators, particularly IL-6, due to reduced mRNA expression. A decrease in ERK, JNK, and p38 MAPK phosphorylation was also observed, interfering with the establishment of the inflammatory response (Choi et al., 2019; Shin et al., 2022).
The mutant strain Streptomyces somaliensis SCSIO ZH66 showed significant changes in the production of biotechnologically relevant secondary metabolites. Compounds derived from α-pyrone, somalimycin, and two known analogs (UFS-19A and urauchimycin D) were capable of inhibiting the production of IL-5 in in vitro tests (Huang et al., 2016; Li et al., 2017; Huayue et al., 2017). This activity may be attributed to substitutions in the bis-lactone ring chains of antimicrobial-type compounds from the depsipeptide class, which likely adjust the physicochemical properties of the compound and alter its biological activity, demonstrating anti-inflammatory activity (Strangman et al., 2009; Li et al., 2017).
The polyketide antibiotic manumycin A, derived from Streptomyces parvulus, inhibits the production of IL-1β, IL-6, and IL-8 in THP-1 cells and monocytes by downregulating pro-inflammatory genes that regulate the expression of these cytokines (Cecrdlova et al., 2016). Additionally, manumycin-derived compounds, named ManA, ManB, Asu, and Col, were able to suppress the expression of pro-inflammatory genes, including Il1b and Tnfa, limiting the production of IL-1β and TNF-α, respectively, and enhancing the anti-inflammatory effect (Hrdý et al., 2020).
The compound ASK2 was isolated from Streptomyces sp. ASK from the rhizosphere of a medicinal plant. ASK2 exhibited various modulatory effects on the immune response associated with antimicrobial activity. One of these effects was the induction of gene expression responsible for IL-12, IFN-γ, and TNF-α in stimulated macrophages, improving phagocytic activity (Lalith et al., 2017).
Streptomyces gramineus strains, associated with the lichen Leptogium trichophorum, produce actinofuranones D-I with anti-inflammatory effects. The actinofuranones produced are derived from rare polyketides, consisting of a skeleton of 2-hydroxy-2-(1-hydroxyethyl)-2,3-dihydro-3(2H)-furanone. These metabolites were able to inhibit the release of IL-6 and TNF-α, with the anti-inflammatory effects associated with the positioning of the hydroxyl substituent on the unsaturated alkyl chains, which possibly adjusts the physicochemical properties of drugs and their biological activities (Ma et al., 2018).
4.2 ANTIOXIDANT ACTIVITY
Some neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by mitochondrial dysfunction and a consequent increase in the production of reactive oxygen species (ROS), which accumulate and generate oxidative stress (Gandi; Abramov, 2012). The main free radicals formed from the metabolism of O2 are superoxide anion (O2*-), hydrogen peroxide (H2O2), and hydroxyl radicals (OH) (Melo et al., 2011), and their increase can cause mitochondrial damage, lipid peroxidation, and genomic damage (Gandi; Abramov, 2012; Leirós et al., 2014).
Antioxidant activity is essential for the natural control of free radical formation (Leirós et al., 2014). The antioxidant effect is regulated by nuclear factor erythroid 2-related factor 2 (NRF-2), which translocates to the nucleus when oxidative imbalance occurs, binding to the Maf protein, and regulating the activation of genes responsible for producing antioxidant enzymes (e.g., superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT)), and anti-apoptotic proteins (Kaspar et al., 2009).
Various studies evaluate the use of compounds isolated from Streptomyces spp. with antioxidant activity, such as anhydroesfoliamycin, naftopiranomycin, 3-epi-5-deoxyenterocine, 5-deoxyentocine, nocardamine, undecylprodigiosin, and metacycloprodigiosin. These compounds exhibit antioxidant activity primarily through the activation of the NRF-2 pathway, which induces the release of an antioxidant response, such as increased production of antioxidant enzymes, reduced formation of ROS, and inhibition of cytosolic Ca2+ uncoupling. Thus, these metabolites allow for a reduction in mitochondrial damage and lipid peroxidation of the membrane, stabilization of mitochondrial membrane potential, improvement of cellular viability, control of cytosolic Ca2+, as well as inhibition of cytochrome C release and caspases, which are responsible for apoptotic responses (Leirós et al., 2014).
NO is produced by macrophages as a mechanism of inflammation mediation, being increased during the inflammatory process and associated diseases (Bourgou et al., 2010). Its function involves inhibition of the pro-inflammatory NF-κB pathway, suppression of inflammatory mediators, regulation of blood flow, among others (Hattori et al., 2004; Naseem et al., 2005; Wallace et al., 2009). Different nitric isoforms are involved in NO production by catalyzing the oxidation of L-arginine to L-citrulline: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). The iNOS isoform is characterized by being calcium-independent, induced by inflammatory cytokines, oxidative stress, and hypoxia (Kashfi, 2018), and its exacerbated expression leads to increased NO production, which, under pathological conditions, becomes a toxic free radical for cells and tissues, leading to oxidative stress and apoptosis (Murakami; Ohigashi, 2007; Bao et al., 2018). Inhibition of its production is a strategy for treating inflammatory diseases.
The compounds streptinone, cyclo-(D)-Pro-(D)-Phe, actinofuranones D-I, and anhydroesfoliamycin, derived from Streptomyces spp., exhibit antioxidant properties by reducing iNOS expression and consequently reducing NO release (Leiros et al., 2014; Ma et al., 2018; Hassan et al., 2020; Gegunde et al., 2021; Lee et al., 2023). Another Streptomyces compound with similar activity is streptoglycerides, which demonstrated inhibitory effects on NO mediators by inhibiting nitrite production, important for NO composition, and by inhibiting iNOS expression (Shin et al., 2022). In contrast to these findings, the compound ASK2 exhibited stimulating activity of NO production by antigen-stimulated macrophages, contributing to the microbicidal activity of NO during phagocytosis (Lalith et al., 2017).
4.3 CELLULAR IMMUNOSUPPRESSION
The goal of immunosuppression is to reduce the innate and adaptive immune response, either naturally or induced, to avoid interference with immunity in certain contexts, such as organ transplantation and autoimmune diseases. Well-established immunosuppressive agents in clinical practice include calcineurin inhibitors (CNI) such as cyclosporine (CsA) and tacrolimus (Tac), which were introduced in the 1980s (Yu et al., 2018; Farouk et al., 2020; Job et al., 2023). However, these inhibitors are associated with severe toxic effects when used long-term, such as nephrotoxicity, neurotoxicity, cancer, and susceptibility to infections (Farouk; Rein, 2020; Pallet, 2021), leading to the search for compounds with fewer adverse effects.
Streptomyces hygroscopicus is responsible for producing over 180 bioactive metabolites, including rapamycin (Li et al., 2014; Salwan; Sharma, 2020). In addition to its antimicrobial properties, rapamycin has been observed and approved for its immunosuppressive activity due to its ability to interact with mTOR (mammalian target of rapamycin) signaling, binding to the FKBP12 protein and inhibiting the proliferation of key cytokines and T cells (Schreiber et al., 2019; Ganesh; Devi, 2023). Rapamycin is indicated for clinical use in post-transplant patients (Sehgal et al., 1975), presenting fewer side effects, such as neurotoxicity and nephrotoxicity, compared to other calcineurin inhibitors (Dang et al., 2017).
(-)-Citoxazone is a rare type of oxazolidinone-2-one isolated from cultures of a Streptomyces sp. strain RK95-31 (Kakeya et al., 1999). Studies indicate that (-)-citoxazone and its derivatives exhibit modulatory effects on cytokines through selective signaling of Th2-type TC4 lymphocytes, specific for human allergens, but not Th1, making it a potent immunotherapeutic agent (Kakeya et al., 1999; Zappia et al., 2007; Miranda et al., 2016).
The enzyme L-asparaginase is an aminohydrolase used in the treatment of Acute Lymphoblastic Leukemia (ALL) and other lymphomas (Balasubramanian et al., 2012). Its mechanism of action involves the hydrolysis of asparagine into aspartic acid and ammonia, inducing nutritional stress and disrupting the cell cycle and proliferation of cancer cells in ALL (Yang et al., 2014). Studies are investigating the production of L-asparaginase by Streptomyces species for commercial use in treating cancer cells, demonstrating its capacity to induce Th1 cytokine production in lymphocytes and activation of cytotoxic T cell subsets, which are effective in immune responses against cancer (Eyileten et al., 2016; Lacerda et al., 2018). A similar effect was observed with ebosina, which also exhibits cellular immunomodulation of CD3 and CD8 T cells, associated with autoimmune diseases such as psoriasis. Reduction in cellular expression was noted with high and medium doses of ebosina, in addition to aiding in the increase of Treg cell expression in the immune response (Zhang et al., 2013; Guo et al., 2021).
4.4 MODULATION OF PHAGOCYTOSIS
Macrophages are the primary phagocytes involved in the immune response, playing roles in homeostasis, defense, and repair throughout all body tissues (Gessain et al., 2020; Gonzales et al., 2023). Prior to activation, they are known as resident tissue macrophages in a stationary state. During phagocytosis, macrophages are responsible for engulfing and metabolizing extracellular material, both "self" and "non-self," such as pathogens, apoptotic bodies, and neoplastic cells, present in the interstitial medium of healthy or diseased tissues (Watanabe et al., 2019; Gessain et al., 2020). Depending on the stimuli, macrophages can manifest different phenotypes, particularly the pro-inflammatory/anti-tumoral (M1) profile dependent on glycolytic metabolism, or the anti-inflammatory/pro-tumoral (M2) profile dependent on glycolytic metabolism or mitochondrial oxidative phosphorylation (Viola et al., 2019).
Macrophage activation is crucial for increased phagocytic activity, making it a suitable target for the immunomodulatory bioactivity of Streptomyces sp. (Vergadi et al., 2017). The compound ASK2 was able to enhance the phagocytic activity of non-activated macrophages, acting as an opsonin against microbial antigens that stimulate immune responses (Lalith et al., 2017). Conagenin also influenced the increase in phagocytic response due to the increased expression of the Fc receptor on the membrane of alveolar macrophages, stimulating phagocytosis (Hamada et al., 1999).
Thiolholgamide A (thioA) is a peptide produced by Streptomyces lividans ΔYA8. This metabolite exhibited activity against mitochondrial morphology, reducing and inhibiting ATP synthase action in cancer cells. Additionally, thioA was effective in inducing increased proliferation of M1-type macrophages, which are antagonistic in cancer processes. Thus, the compound has emerged as a strong candidate as an anti-tumor antiproliferative agent and macrophage modulator (Dahlem et al., 2020).
5 CONCLUSION
The genus Streptomyces is a major focus of research in the biotechnology and pharmaceutical industries due to the bioactivities of its metabolic products, which are of interest across various sectors. It has been observed that this genus has enabled the development of a range of clinically used antimicrobials, which are now employed in the therapeutic management of various infections. Additionally, the metabolites produced by Streptomyces sp. have the potential to act as immunomodulatory enhancers against diseases, optimizing and regulating the immune system's function.
ACKNOWLEDGMENTS
FAPEMA and Ceuma University for financial and logistical support.
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Abstract
Objective: To carry out a bibliographical survey, through a narrative literature review, on the use of secondary metabolites of Streptomyces sp. as an immunomodulatory agent. Results and Discussion: Actinobacteria (phylum Actinomycetota) represent Gram-positive, filamentous, spore-forming bacteria that produce secondary metabolites, compounds that offer an advantage in the growth, reproduction and perpetuation of the microorganism, especially in environments in which there is ecological competition for nutrients and for territory between different species. These metabolites are notably known for their important antimicrobial action, having great utility in clinical, pharmaceutical and industrial settings. More than 10,000 bioactive compounds have already been obtained from actinobacteria, where approximately 75% of them come from the Streptomyces genus, currently responsible for the production of approximately 80% of antibiotics on the market, with great clinical importance. In addition to antimicrobial activity, several studies seek to identify the activity of secondary metabolites of Streptomyces sp. as immunomodulators of the immune response, positively or negatively regulating the chain of events that is established during an aggressive stimulatory process. Conclusion: The genus Streptomyces is one of the focuses of studies in the biotechnology and pharmaceutical industry because its metabolite products present bioactivities of interest to different sectors. The metabolites produced by Streptomyces sp. They have the potential to act as an immunomodulatory booster against diseases, optimizing and regulating the work of the immune system. Research Implications: The practical and theoretical implications of this research are discussed, providing insights into how the results can be applied or influence practices in the field of biotechnology. These implications may cover the areas of microbiology, pharmacy, medicines. Originality/Value: This study contributes to the literature by addressing the importance of selecting microorganisms with biological activity. The relevance and value of this research are evidenced when it shows the capacity and versatility of microorganisms of industrial interest.