Streptomycetes in Soil: Community Signals for Biotechnology

OPINION article Front. Microbiol., 20 August 2013Sec. Antimicrobials, Resistance and Chemotherapy Volume 4 - 2013 | https://doi.org/10.3389/fmicb.2013.00240

The increase of antibiotic resistance together with the gap in the discovery of new antibiotics is an alarming problem. An increase of mortality worldwide caused by antimicrobial resistance has been estimated by 2050. Hence, actions need to be taken now to minimize this important problem. Among the different strategies, the chemical diversification of clinically used antibiotics is a powerful approach to accelerate the discovery of new efficient antibiotics. During my Ph.D., we aimed to modify aminoglycoside antibiotics, such as paromomycin and kanamycin, by inducing catalytic-driven regioselective oxidation at the C3 position of the glucose-configured residue, as previously developed in our group. In this way, a 3-keto-sugar is obtained which can undergo several chemical modifications leading to modified aminoglycosides. From this, we wished to synthesize derivatives that could overcome the resistance induced by phosphoryl transferase enzymes (APH3’) and maintain a good antibiotic potency. The synthesized aminoglycoside derivatives have been tested on several E.coli strains containing different subtypes of the gene coding for APH3’ to determine their effectiveness towards bacterial strains expressing the resistant enzyme. Next to this, cell-free translation assays have been performed to gain information on whether the newly synthesized aminoglycoside derivatives maintain the targeting activity for their parental compounds. Additional studies such as co-crystallization with a clinical relevant resistant isoenzyme and biochemical assays have also been investigated to determine the efficiency of the modification in avoiding the resistance mechanism at the enzymatic level. The results of the synthetic approaches and the biological/biochemical assays are reported in this thesis.

The need for the discovery of new antibiotics and solving the antibiotic resistance problem requires rapid detection of antibiotics, identification of known antibiotics, and prediction of antibiotic mechanisms. The bacterial lux genes encode proteins that convert chemical energy into photonic energy and lead to bioluminescence. Exploiting this phenomenon, we constructed a lux-based bioluminescence system in Staphylococcus aureus by expressing lux genes under the control of stress-inducible chaperon promoters. When experiencing antibiotic stress, these constructed reporter strains showed clear bioluminescence response. Therefore, this bioluminescence screening system can be used for the detection of antibiotics in unknown chemical mixtures. Further analysis of bioluminescence response patterns showed that: (1) these bioluminescence response patterns are highly antibiotic specific and therefore can be used for rapid and cheap identification of antibiotics; and that (2) antibiotics having the same mechanism of action have similar bioluminescence patterns and therefore these patterns can be used for the prediction of mechanism for an unknown antibiotic with good sensitivity and specificity. With this bioluminescence screening assay, the discovery and analysis of new antibiotics can be promoted, which benefits in solving the antibiotic resistance problem.

Antibiotic resistance is a major global health threat that requires the discovery of new and effective antibiotics. However, the traditional methods of antibiotic discovery are slow, costly, and inefficient. This minireview presents the discovery of a new class of antibiotics using AI, which is a powerful and innovative tool for accelerating and enhancing the drug discovery process. A web-based search was used to extract data. The new antibiotics were identified by a deep learning model that can learn from the graph representation of chemical structures, and that can also provide explainable and interpretable predictions of antibiotic potency. The new antibiotics have novel and diverse chemical structures and mechanisms of action, which are unlike any existing class of antibiotics. The new antibiotics have shown promising activity against a wide range of drug-resistant bacteria, both in vitro and in vivo and have a low propensity to induce resistance. The discovery of the new antibiotics demonstrates the potential of AI in antibiotic discovery, and also opens up new avenues and opportunities for further research and innovation in this field. However, there are also several challenges and limitations that need to be overcome before the new antibiotics can be translated into clinical use, such as ensuring their safety and efficacy in humans, optimizing their pharmacokinetics and pharmacodynamics, and scaling up their production and distribution. The article stresses on crucial issues by highlighting the importance of ethical principles, guidelines, and regulations that can ensure the responsible and ethical use of AI in medicine.

Exploring untapped potential of Streptomyces spp. in Gurbantunggut Desert by use of highly selective culture strategy

There is a real consensus that new antibiotics are urgently needed and are the best chance for combating antibiotic resistance. The phylum Actinobacteria is one of the main producers of new antibiotics, with a recent paradigm shift whereby rare actinomycetes have been increasingly targeted as a source of new secondary metabolites for the discovery of new antibiotics. However, this review shows that the genus Streptomyces is still the largest current producer of new and innovative secondary metabolites. Between January 2015 and December 2020, a significantly high number of novel Streptomyces spp. have been isolated from different environments, including extreme environments, symbionts, terrestrial soils, sediments and also from marine environments, mainly from marine invertebrates and marine sediments. This review highlights 135 new species of Streptomyces during this 6-year period with 108 new species of Streptomyces from the terrestrial environment and 27 new species from marine sources. A brief summary of the different pre-treatment methods used for the successful isolation of some of the new species of Streptomyces is also discussed, as well as the biological activities of the isolated secondary metabolites. A total of 279 new secondary metabolites have been recorded from 121 species of Streptomyces which exhibit diverse biological activity. The greatest number of new secondary metabolites originated from the terrestrial-sourced Streptomyces spp.

Mining novel Streptomyces species from extreme environments provides a valuable strategy for the discovery of new antibiotics. Here, we report a strain of Streptomyces sp. HMX87T, which exhibits antimicrobial activity and was isolated from desert soil collected in the Tuha Basin, China. Molecular taxonomic analysis revealed that the 16S rRNA gene sequence of strain HMX87T shares the highest similarity with those of Streptomyces bellus CGMCC 4.1376T (98.5%) and Streptomyces coerulescens DSM 40146T (98.43%). In phylogenetic trees, it formed a distinct branch. The average nucleotide identity (ANI) and digital DNA–DNA hybridization (dDDH) values between strain HMX87T and the above two type strains were below the thresholds of 95% and 70%, respectively, confirming that strain HMX87T represents a novel species within the genus Streptomyces, for which the name Streptomyces hamibioticus sp. nov. is proposed. Physiologically, the strain HMX87T grew at temperatures ranging from 25 to 37 °C, tolerated pH values from 5 to 12, and survived in NaCl concentrations of 0% to 8% (w/v). Chemotaxonomic characterization indicated the presence of LL-diaminopimelic acid (LL-DAP) in the cell wall, ribose and galactose as whole-cell hydrolysate sugars, MK-9(H8) (66.3%) as the predominant menaquinone, and iso-C16:0 (25.94%) and anteiso-C15:0 (16.98%) as the major fatty acids characteristics that clearly distinguish it from its closest relatives. Whole-genome sequencing of strain HMX87T revealed an abundance of genes associated with high-temperature tolerance, salt-alkali resistance, and antimicrobial activity. The genomic features and secondary metabolic potential reflect its adaptation to extreme environmental conditions, including high temperature, salinity, alkalinity, strong ultraviolet radiation, and oligotrophic nutrients. The strain HMX87T has been deposited in the Czech Collection of Microorganisms (CCM 9454T) and the Guangdong Microbial Culture Collection Center (GDMCC 4.391T). The 16S rRNA gene and whole-genome sequences have been submitted to GenBank under accession numbers PQ182592 and PRJNA1206124, respectively.

Because of the special living environment, marine-derived actinomycetes, especially the genus Streptomyces, possess distinct and complex metabolic capabilities, resulting in wide diversity of their secondary metabolites in chemical structures and biological activities.1 Among them, many valuable lead compounds were obtained for discovery of new antibiotics.2, 3, 4 Bafilomycins are a family of polyene macrolides containing a 16-member lactone ring. Thirteen bafilomycin antibiotics have been isolated, including bafilomycins A1, A2, B1, B2, C1 and C2 from Streptomyces griseus sp. sulphurus (TU 1922),5 bafilomycins D and E from S. griseus TU 25996 and bafilomycins F–J from Streptomyces spp.7 Among them, bafilomycins D and E contain the ring-opened side chain different from other bafilomycins. Bafilomycins have antibacterial, antifungal, antineoplastic and immunosuppressive activities.5 Some bafilomycins are specific inhibitors of vacuolar-type H+-ATPase (V-ATPase),8, 9, 10, 11 in which bafilomycin A1 is the most used. Being a specific inhibitor of V-ATPase, bafilomycin A1 can prevent the re-acidification of synaptic vesicles once they have undergone exocytosis. In addition, bafilomycin A1 has antimalarial activity.12 Bafilomycins B1 and C1 have been mentioned as potential antiosteoporotic agents in treating bone lytic diseases.

Screening new naturally occurring biologically active compounds is an effective strategy for creating a portfolio of platforms for developing new chemical agents against multidrug-resistant microbial strains. Actinomycetes are an extremely prolific source of structurally diverse secondary metabolites, most of which have pharmaceutical or biotechnological significance. Among them, the genus Streptomyces stands out, producing about 55 % of all known naturally occurring antibiotics. However, due to the significant redisco­very of already known compounds, especially among actinomycetes, the rate of discovery of new antibiotics has slowed considerably. Today, there is growing interest in screening biologically active compounds from poorly studied and extreme habitats. In this study, we demonstrated the phylogeny, bioactivity and dereplication of secondary metabolites of the Je 1-93 strain isolated from the rhizosphere soil of juniper (Juniperus excelsa Bieb.). Phylogenetic analysis of the Je 1-93 strain based on the nucleotide sequence of the 16S rRNA gene allowed its identification in the Streptomyces genus and showed the greatest similarity with the S. hydrogenans CA04 strain (100 % identity). Analysis of the antimicrobial activity of this strain showed its strong antifungal activity against the reference Candida albicans ATCC 885-653 strain as well as the multi-resistant C. albicans №12 strain, which is resistant to nystatin, amphotericin B, clotrimazole, itraconazole, ketoconazole and fluconazole. To identify compounds that probably provide antifungal activity, we analysed secondary metabolites produced by Streptomyces sp. Je 1-93. To facilitate dereplication, the obtained extracts of secondary metabolites were separated by size-exclusion chromatography on a column filled with Sephadex LH-20. Methanol was used as the mobile phase. As a result of the dereplication analysis in the database of natural compounds (Dictionary of Natural Products), antibiotic antimycins were found among the secondary metabolites in the extract of the Je 1-93 strain, and they have a high probability of providing the antifungal activity of this strain.

Soil microbial communities are pivotal to plant health and nutrient acquisition. It is becoming increasingly clear that many interactions, both among and between microbes and plants, are governed by small bioactive molecules or "secondary metabolites" that can aid in communication, competition, and nutrient uptake. Yet, secondary metabolite biogeography - who makes what, where, and why-is in its infancy. Further, secondary metabolite biosynthesis genes are often silent or weakly expressed under standard laboratory conditions, making it incredibly difficult to study these small molecules. To begin to address these dual challenges, we focused on redox-active metabolites (RAMs), a specific class of small molecules, and took advantage of recent findings that many RAMs aid in acquiring phosphorus and that their production is frequently stimulated by stress for this macronutrient. We developed a screen for RAM-producing bacteria that leverages phosphorus limitation to stimulate metabolite biosynthesis and uses a colorimetric (ferrozine) iron-reduction assay to identify redox activity. We isolated 557 root-associated bacteria from grasses collected at sites across the United States (Santa Rita Experimental Range [AZ], Konza Prairie Biological Station [KS], and Harvard Forest [MA]) and from commercial tomato plants and screened them for RAM production. We identified 128 soil isolates of at least 19 genera across Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes that produced RAMs under phosphorus stress. Our work reveals that the production of RAMs under phosphorus stress is common across diverse soil bacteria and provides an approach to screen for these small molecules rapidly.IMPORTANCEBy secreting secondary metabolites, bacteria at the plant root can defend against diseases and help acquire essential nutrients. However, the genes that synthesize secondary metabolites are typically inactive or are weakly expressed under standard laboratory conditions. This fact makes it difficult to study these small molecules and hinders the discovery of novel small molecules that may play crucial roles in agricultural and biomedical settings. Here, we focus on redox-active metabolites (RAMs), a class of secondary metabolites that can help bacteria solubilize phosphorus and are often produced when phosphorus is limited. We developed a screen that rapidly identifies RAM-producing bacteria by utilizing a colorimetric iron-reduction assay in combination with phosphorus limitation to stimulate biosynthesis. The screen reveals that RAM-producing bacteria are far more prevalent in soil than previously appreciated and that this approach can be used to identify RAM producers.

In the 21st century, the world is facing persistent global problems that have led to 193 countries to agree on the 17 Sustainable Development Goals (SDGs). The United Nations introduced these goals in 2015 to find solutions that could help end poverty, promote prosperity and protect the planet (United Nations, 2016a). In this brief perspective, we will discuss the potential role of Streptomyces in achieving those SDGs, focusing it in the current strategies applied for discovering novel compounds and in some of the problems that must be faced (Figure 1). Members of the genus Streptomyces are filamentous Gram-positive bacteria belonging to the phylum Actinobacteria. They are ubiquitous microorganisms mainly found in soil but they can also inhabit other niches like seawater or deserts, or living associated with other organisms (Sivalingam et al., 2019). Streptomyces is mainly known for its ability to produce a wide array of bioactive secondary metabolites, which have several interesting applications in different fields (Alam et al., 2022; Demain & Sanchez, 2009; Donald et al., 2022). One of the problems that most concern the United Nations is the existence of a growing demand for food in today's world (Food security information network, 2023). In this context, Streptomyces could play a relevant role in achieving SDG 2 (zero hunger, improved nutrition and sustainable agriculture) and SDG 1 (end poverty). Streptomyces produces several metabolites with significant commercial relevance in enhancing the nutritional value of human food and animal feed, such as vitamins like cobalamin (Rex et al., 2022). Additionally, there is an increasing need for enzymes in the global market (Grand View Research, 2023). Streptomyces due to its wide metabolic potential is used for the sustainable biotechnological production of a broad assortment of enzymes such as proteases, xylanases, amylases, lipases, keratinases, cellulases, dextranases and chitinases among others (Fernandes de Souza et al., 2022; Kumar et al., 2020). These enzymes have applications in several fields, and advantages not only in terms of energy consumption, stability, substrate specificity, purity or reaction efficiency but also in ecological and waste generation, thus contributing to the achievement of sustainable industrialization and innovation (SDG 9) and promoting responsible production and consumption (SDG 12). An example of enzymes with ecological applications is the degradation of lignocellulose and dye decolourization by detergent-stable peroxidases and laccases (Cuebas-Irizarry & Grunden, 2024). These enzymes can be potentially used to treat wastewater resulting from human activities like textile and paper industries, which cause environmental pollution and wastes that affect life below water (SDG 14). Another promising application of Streptomyces is its use to obtain energy from waste resources, what contributes to the pursuit of affordable and clean energy (SDG 7) and climate action (SDG 13). For instance, Muthusamy et al. (2019) were able to produce bioethanol from different agro-residues using an S. olivaceus strain isolated from a mangrove sample. Streptomyces also contributes to the preservation of life on land (SDG 15) because they play a crucial role in sustainable agriculture and plant growth due to its participation in soil fertility (Hozzein et al., 2019). They contribute to phosphate and potassium biosolubilization, nitrogen supply to ecosystems, to stablish beneficial symbiosis with other rhizosphere microorganisms and to produce biocontrol agents such as phytohormones, antimicrobials, antifungals, pesticides, bioherbicides and insecticides (Boubekri et al., 2022; Li et al., 2021). Furthermore, the use of Streptomyces is considered an eco-friendly and promising technology for bioremediation of contaminants like pesticides and heavy metals because they can degrade organic and inorganic compounds more efficiently and safely than chemical agents (Jagannathan et al., 2021). Nevertheless, the greatest contribution throughout history of Streptomyces is as producer of bioactive compounds with applications in clinical, veterinary and agricultural fields, being the most important microbial source of bioactive compounds (Donald et al., 2022). In this context, this microorganism is an incredible force for achieving good health and well-being (SDG 3). During the so-called Golden Age of antibiotic discovery Streptomyces provided humanity with antibiotics, antifungal, anti-parasitic, immunosuppressive agents and antitumor compounds, many of them currently used in clinical (Demain & Sanchez, 2009). Subsequently, limitations in classical search techniques and depletion of traditional habitats have led to the rediscovery of known compounds or the identification of a scarce number of compounds with new scaffolds. This, together with the high costs to develop new compounds for clinical and other uses, resulted in a drastic decline in the discovery of new drugs and the withdrawal of these research departments from some big pharma companies (Genilloud, 2017). Nevertheless, recent screening new approaches, such as the use of pathogenic bacteria conditionally expressing antisense RNA of essential genes, have led to discovering new antibiotics like platensimycin (Figure 2) (Genilloud, 2017). In addition, screening antibiotic active molecules for other activities identified a number of useful natural products (NPs), including some with antitumor activity such as actinomycin D (Figure 2) (Demain & Vaishnav, 2011). Subsequently, advances in -omics and sequencing methods, and the development of synthetic and genomic manipulation techniques in Streptomyces in the last decades, have led to the emergence of new strategies in drug discovery, such as genome mining and combinatorial biosynthesis. These approaches represent promising strategies for discovering novel bioactive NPs, in many cases with high structural diversity. Additionally, these strategies were improved when combined with the isolation of new Streptomyces strains from low explored environments, which produce structurally diverse bioactive NPs with potential clinical applications (Alam et al., 2022; Chen et al., 2021; Donald et al., 2022; Lacey & Rutledge, 2022; Qin et al., 2017; Quinn et al., 2020). Noteworthy, the antibacterial anti-Gram positive chaxalactin (Figure 2) (Castro et al., 2018) produced by Streptomyces leuwenhoeeki from the Atacama desert; or cervimycins produced by Streptomyces tendae strain HKI 0179 from the ancient Italian cave Grotta dei Cervi, with antibacterial activity anti-MRSA, anti-VRE and anti- S. aureus EfS4 (Herold et al., 2005). Notably, in recent years, marine environments have been a prolific source of new NPs with a variety of bioactivities (Alves et al., 2018; Chen et al., 2021; Choudhary et al., 2017; Dharmaraj, 2010; Donald et al., 2022; Yang et al., 2020). Examples include the antibacterial anthracimycin B, produced by Streptomyces cyaneofuscatus M-169 from the Cantabrian sea (Rodríguez et al., 2018); or the cytotoxic neo-actinomycin A produced by Streptomyces sp. IMB094 from a marine sediment (Wang et al., 2017). Another unusual habitat where Streptomyces strains are found is in symbiotic associations with plants, fungi, vertebrates or invertebrate animals, both marine and terrestrial. In these associations, they appear to be a nutritional resource, or to play a protective role for the host against pathogens, parasites or predators, by producing antibiotic compounds (Barka et al., 2016; Batey et al., 2020; Chen et al., 2021; Donald et al., 2022; Qin et al., 2011; Seipke et al., 2012). In this context, it is worth highlighting the role played by some volatile compounds (VOCs) produced by Streptomyces such as geosmine, as an attractant for soil-dwelling arthropods like springtails, to localize them as a food source. In turn, springtails facilitates the dispersal of Streptomyces spores to other niches by these arthropods (Becher et al., 2020). One of the most widespread example is the symbiotic relationship with insects. Thus, new antifungal compounds such as mycangimycins (Scott et al., 2008) or frontalamides A and B (Blodgett et al., 2010) have been isolated. Both are produced by symbiotic Streptomyces strains found in the southern pine beetle (SPB) Dendroctonus frontalis. Another example are the new formicamycins antibiotics (Figure 2) that have shown promising anti-MRSA and VRE activities, which are produced by Streptomyces formicae KY5, isolated from African ants of the Tetraponera genus (Qin et al., 2017). As it has been mentioned before, genome mining has become a useful tool for discovering natural products from the early 2000s (Baltz, 2021; Lee et al., 2020). It can be defined as the set of bioinformatics tools used to detect secondary metabolite biosynthesis gene clusters (smBGCs) and their possible functional and chemical interactions (Albarano et al., 2020). Genome mining has shown that each Streptomyces species possesses about 30 smBGCs, what has supported the hypothesis that most Streptomyces biodiversity is yet to be exploited for NPs discovery (Baltz, 2019; Belknap et al., 2020). In recent years, this strategy has enabled the identification of potentially new secondary metabolites encoded by smBGCs. For example, the antitumor chaxapeptin, identified by mining a S. leuwenhoeeki strain isolated from the Atacama desert (Castro et al., 2018); the antituberculous atratumycin, produced by S. atratus SCSIO ZH16 from the South China Sea (Sun et al., 2019); the new cytotoxic peptide curacozole (Figure 2), isolated from Streptomyces curacoi (Kaweewan et al., 2019); or largimycins, new leinamycin-like compounds identified by mining S. argillaceus (Becerril et al., 2020). Nonetheless, despite some successful examples that can be found in the literature, the enormous diversity of smBGCs identified by genome mining is only partially translated to discovering new bioactive NPs, and identifying and characterizing compounds encoded by these predicted smBGCs still requires substantial laboratory work. Thus, the smBGC can be expressed or low-expressed but the predicted encoded compounds is not detected under standard laboratory conditions (cryptic products), or the smBGC identified is not expressed and the product is unobserved (silent BGC with a cryptic product). All of these scenarios exemplify 'Known Unknowns' secondary metabolites (Hoskisson & Seipke, 2020). Therefore, a key issue for being successful using genome mining as an approach is to find strategies to turn on or to increase the expression of these silent or low expressed smBGCs. For this purpose, there are several genetic strategies that have been used like overexpression of positive regulators; inactivation of negative regulators; heterologous expression of the smBGC; or the insertion of a strong promoter upstream of BGC operons (Olano, García, et al., 2014). Other strategies to alleviate challenge of identifying the cryptic products are OSMAC (one strain of many compounds) (Pan et al., 2019); mimicking the ecological environment of the producer (Cuervo et al., 2022); redirecting precursors to the target biosynthesis pathway (Kallifidas et al., 2018); engineering global regulators (Cuervo et al., 2023); or ribosome engineering (Zhu et al., 2019). Nevertheless, we have to keep in mind that one of the major bottlenecks in drug discovery throughout history was the constant rediscovery of known compounds. From this perspective, some smart bioinformatics genome mining approaches can increase the chances to identifying unknown smBGCs encoding new compounds with potentially clinical applications. For example, several strategies have been used in recent years like mining for resistance genes (Culp et al., 2020), or for Streptomyces Antibiotic Regulatory Protein genes (Ye et al., 2023). Additionally, searching genes involved in the biosynthesis of unusual functional groups has also been used as an approach to select new smBGCs, such as targeting halogenases genes (Prado-Alonso et al., 2022); DNA regions in Polyketide Synthases encoding the didomain DUF–SH specific for sulfur incorporation (Pan et al., 2017); C-terminal thioester reductase (TR) domains and ϖ-transaminases (Awodi et al., 2017); or piperazate synthase encoding genes (García-Gutiérrez et al., 2024; Morgan et al., 2020). Another important application of genome mining is as reservoir of genetic sets and devices for being used in combinatorial biosynthesis strategies. This method squeezes the maximum of synthetic biology techniques, by using different genetic engineering strategies to generate smBGCs with novel gene combinations. These would encode novel biosynthetic pathways that potentially could direct the biosynthesis of new natural products with different or improved properties. Combinatorial biosynthesis encompasses several strategies such as combination of native biosynthetic genes and genes from other smBGCs, expression of genes from other smBGCs into mutants blocked at specific biosynthetic steps, mutasynthesis based on the use of different biosynthetic precursors, or all of the above strategies combined to obtain new structural units (Olano et al., 2009). This method has been successfully used for the biosynthesis of new derivatives of a wide variety of compounds like terpenes (Tang et al., 2022), non ribosomal peptides (Ruijne & Kuipers, 2021), RiPPs (ribosomal synthesized and post-translationally modified peptides) (Sardar & Schmidt, 2016), polyketides (Wang et al., 2022) or nucleosides (Niu et al., 2017). An interesting example was the generation of the new glycosylated analog demycarosyl-3D-β-D-digitoxosylmithramycin SK (Figure 2), derived from mithramycin (Núñez et al., 2012). Production of this compound was achieved by providing the capability to synthesize D-digitoxose to a S. argillaceus strain mutated in a ketoreductase gene of the mithramycin BGC. This analog showed high antitumor activity and less toxicity than the parental compound, and among others, it is able to suppress EWS-FLI1 activity suggesting a potential development in clinical (Osgood et al., 2016). Another example was the production of epirubicin (Figure 2), a less cardiotoxic doxorubicin derivative, which initially was produced by semisynthesis. A new method was designed for its production consisting in expressing avrE or eryBIV from the avermectin and erythromycin gene clusters into a S. peucetius doxorubicin non-producer mutant (Demain & Vaishnav, 2011). To summarize the current state of the art we can highlight a study carried out by Malmierca et al. (2018, 2020), which illustrates the combination of different chromatographic, genome mining, nutritional and combinatorial biosynthesis approaches, as an effective strategy for identifying new NPs. This research was conducted on Streptomyces strains isolated from symbiotic associations with leaf cutters ants of the Attini tribe. These ants maintain close association with Streptomyces that produce bioactive compounds, including antifungals and inhibitors of Escovopsis weberi, a parasitic microfungus of their mutualistic Basidiomycete fungi (Seipke et al., 2011). Malmierca et al. mined those Streptomyces genomes searching for smBGCs encoding glycosylated secondary metabolites, since many therapeutically relevant drugs contain sugar moieties (Salas & Méndez, 2007). By a combination of genome mining, PCR screening, metabolites dereplication, as well as genetic and nutritional approaches, they identified two novel compounds of the cervimycins family (sipanmycin A and B), and two novel members of the warkmycin family (Malmierca et al., 2018). Also, by combinatorial biosynthesis, expressing plasmids for the biosynthesis of deoxysugars into the sipanmycin producer Streptomyces CS149, they generated six different derivatives with altered glycosylation patterns (Malmierca et al., 2020). Recent research, some of them summarized in this Editorial article suggest that Streptomyces remains the leading producer of bioactive compounds. This article emphasizes the contribution of these microorganisms to achieving SDG3. Moreover, recent years have seen the implementation of new methods that have revitalized the discovery of new natural products, accentuating the promising potential of Streptomyces. Even though, despite the discovery of new Streptomyces species and the identification of a large number of hypothetical smBGCs through genome mining research, only a small fraction of them have been characterized so far. This is mainly due to the limitations of these methods. For example, culturing new Streptomyces species from extreme environments under laboratory conditions is usually a challenge, as well as the heterologous expression of smBGCs, which is difficult and time-consuming. Related to genome mining, one of the major issues is the quality of genomic sequences. Most of the sequences in public databases are in draft form. Although incomplete genome sequences may be adequate for assembling many small, non-repetitive secondary metabolites smBGCs, they are unsuitable for large smBGCs like those encoding NRPS or type I PKS. These enzymes are typically involved in the biosynthesis of most compounds identified in drug discovery programs. Consequently, their encoding genes are often predicted to be scattered through several contigs, making challenging to identify the corresponding smBGCs (Baltz, 2021). Another drawback is that although powerful methods for the prediction of product structure from sequences exist, like antiSMASH (Blin et al., 2023), PRISM (Skinnider et al., 2020) or MIBiG (Terlouw et al., 2023) among others, they still have a relative high rate of false positives and generally are limited to identify smBGCs related to known ones. Moreover, once hypothetical smBGCs have been located, it remains a huge challenge to activate them. Additionally, predicting smBGCs is worthless without linking them to their final product and/or expected biological activities (Lee et al., 2020; Olano, Méndez, & Salas, 2014; Ren et al., 2017). On the other hand, it is interesting to note that although the new strategies developed in Streptomyces have shown the potential to discover pharmaceutically important drugs, they have not been successfully integrated into pharmaceutical company pipelines. This could be due to several factors, such as low throughput fermentation, challenges in natural product optimization, and declining return on investment (Baltz, 2021; Ward & Allenby, 2018). Miriam Rodríguez: Writing – original draft; writing – review and editing. Lorena Cuervo: Writing – original draft. Laura Prado-Alonso: Writing – original draft. María Soledad González-Moreno: Writing – original draft. Carlos Olano: Writing – review and editing; funding acquisition. Carmen Méndez: Writing – review and editing; funding acquisition. This work was granted by a grant from the Spanish Ministry of Science and Innovation (PID2020-113062RB-100) to CM, and by a grant from the Spanish Ministry of Science, Innovation, and Universities to CO (RTI2018-093562-B-I00). The authors declare no competing financial interest.

The emergence of antibiotic-resistant bacteria has limited treatment options and led to the untreatable infections, thereby necessitating the discovery of new antibiotics to battel against bacteria. Natural products from endophytic actinobacteria (EA) serve as a reservoir for discovery of new antibiotics. Therefore, the current study focused on the isolation and antibacterial properties of EA isolated from Luffa cylindrica. Six strains were identified using morphological characterization, SEM analyses and 16S rRNA gene sequencing from the roots and leaves of the plant. They were taxonomically classified as Streptomycetaceae family. This is the first report on EA form L. cylindrica. The strains produced a chain of oval, cubed or cylindrical shaped spores with spiny or smooth surfaces. Three strains; KUMS-B3, KUMS-B4 and KUMS-B6 were reported as endophytes for the first time. Fifty percent of isolates were isolated from leaves samples using YECD medium. Our results showed that the sampling time and seasons may affect the bacterial diversity. All six strains had antibacterial activity against at least one of the tested bacteria S. aureus, P. aeruginosa, and E. coli. Among the strains, KUMS-B6 isolate, closely related to S. praecox, exhibited the highest antibacterial activity against both gram-positive and negative bacteria. KUMS-B6, KUMS-B5 and KUMS-B4 isolates strongly inhibited the growth of P. aeruginosa. Interestingly, the strains, isolated from leaves exhibited stronger antagonist activities compared to those isolated from the roots. The study revealed that the isolated strains from Luffa produce a plethora of bioactive substances that are potential source of new drug candidates for the treatment of infections.

Unlocking the synergistic potential of green metallic nanoparticles and antibiotics for antibacterial and wound healing activities.

Antibiotic resistance is one of the growing concerns in healthcare settings. Most of the clinical and community (bacterial) strains have grown immune to almost all the available antibiotics. The discovery of new antibiotics or resurging of available antibiotics has failed to outcompete the growing resistance within the bacterial community. Thus, finding an alternative antibacterial modality to treat infectious diseases has become a significant objective among the scientific community around the globe. Phage therapy is one such an antibacterial therapy for the treatment of severe bacterial infections. The bacteriophages (or phage) are viruses that prey on bacteria for their multiplication and survival. Discovery of bacteriophage dates back to the early 1910s when Frederick W. Twort and Felix d'Herelle observed bacteriolytic activity. Before the discovery of antibiotics, phages were the choice of treatment against bacterial infections, but with the inconsistent research, phage therapy lost its importance in the therapeutics. With the emergence of antibiotic resistance, phage therapy and phage research has got a shape to revolutionize the growing bacterial infections. Phage therapy has shown promising results against severe bacterial infections in the circumstances where antibiotic treatment is ineffectual. This emergency has shed light on this forgotten therapy. This chapter will elucidate the history and fundamentals of phage biology and its significance in treating infectious diseases. With the special focus on advancements in phage research and their clinical outcomes which supports the use of phage therapy in humans. It also deals with the regulatory inputs required for phage therapy and the commercialization strategies undertaken by pharmaceuticals in the globalization of phage medicine. Besides, the authors would like to brief on the personalized phage therapy and their evolution from lab to bedside endpoints for treating the patients and other future perspectives that hold promise.

Change of microbial communities in heavy metals-contaminated rhizosphere soil with ectomycorrhizal fungi Suillus luteus inoculation