Enhanced production of extracellular L-methioninase by entire cell immobilization of Streptomyces MDMMH4 and examination of its utilization as an antioxidant agent.

Streptomyces MDMMH4 cells were immobilized in various matrices with two different techniques for the enhanced and semi-continuous production of extracellular L-methioninase. Of these, agarose was proven to be the most suitable matrix for the immobilization of cells. The optimal agarose concentration was approximately 3% and the initial cell concentration was 150mg/ml (wet cell weight). Agarose-entrapped cells increased the enzyme yield by 21% compared to the highest yield obtained with free cells. Even after twelve successive and efficient fermentation operations, the agarose blocks had good stability. They maintained 69.3% of the enzyme yield obtained in the first cycle. Applying this process on an industrial scale using agarose-entrapped cells, an inexpensive and renewable matrix will allow the stable production of L-methioninase. The purified L-methioninase could be successfully obtained after applying the purification protocol as mentioned in the previous studies. Subsequently, the purified enzyme showed that L- methioninase possessed moderate scavenging activity with high IC50 values of 390.4µg/mL (corresponding to 11.62U/mL). To our knowledge, this is the first report on L-methioninase production by whole-cell immobilization.

The virulome of Streptomyces scabiei in response to cello-oligosaccharide elicitors.

The development of spots or lesions symptomatic of common scab on root and tuber crops is caused by few pathogenic Streptomyces with Streptomyces scabiei 87-22 as the model species. Thaxtomin phytotoxins are the primary virulence determinants, mainly acting by impairing cellulose synthesis, and their production in S. scabiei is in turn boosted by cello-oligosaccharides released from host plants. In this work we aimed to determine which molecules and which biosynthetic gene clusters (BGCs) of the specialized metabolism of S. scabiei 87-22 show a production and/or a transcriptional response to cello-oligosaccharides. Comparative metabolomic analyses revealed that molecules of the virulome of S. scabiei induced by cellobiose and cellotriose include (i) thaxtomin and concanamycin phytotoxins, (ii) desferrioxamines, scabichelin and turgichelin siderophores in order to acquire iron essential for housekeeping functions, (iii) ectoine for protection against osmotic shock once inside the host, and (iv) bottromycin and concanamycin antimicrobials possibly to prevent other microorganisms from colonizing the same niche. Importantly, both cello-oligosaccharides reduced the production of the spore germination inhibitors germicidins thereby giving the 'green light' to escape dormancy and trigger the onset of the pathogenic lifestyle. For most metabolites - either with induced or reduced production - cellotriose was revealed to be a slightly stronger elicitor compared to cellobiose, supporting an earlier hypothesis which suggested the trisaccharide was the real trigger for virulence released from the plant cell wall through the action of thaxtomins. Interestingly, except for thaxtomins, none of these BGCs' expression seems to be under direct control of the cellulose utilization repressor CebR suggesting the existence of a yet unknown mechanism for switching on the virulome. Finally, a transcriptomic analysis revealed nine additional cryptic BGCs that have their expression awakened by cello-oligosaccharides, suggesting that other and yet to be discovered metabolites could be part of the virulome of S. scabiei.

Tetrodecadazinone, a novel tetrodecamycin-pyridazinone hybrid with anti-liver fibrosis activity from Streptomyces sp. HU051.

Tetrodecadazinone (1), a novel tetrodecamycin-pyridazinone hybrid possessing a new 1,2-dimethyl-1-(2-methylnonyl)decahydronaphthalene skeleton, and 4-hydroxydihydrotetrodecamycin (2) were separated from a culture of Streptomyces sp. HU051, together with a known compound, dihydrotetrodecamycin (3). Diverse spectroscopic approaches were applied to assign the structures of 1-3, and the structure of 1 was further confirmed by single crystal X-ray diffraction analysis. Compound 1 is the first example of a pyridazinone-containing natural product. Biosynthetically, 1 is proposed to be derived from a Michael addition reaction of a PKS-derived tetrodecamycin and a piperazic-acid-derived pyridazinone. Biological evaluation revealed 1 could reduce the expressions of extracellular matrix proteins (fibronectin and collagen I) and α-smooth muscle actin (α-SMA) in transforming growth factor-ß (TGF-ß1)-activated LX-2 cells. Preliminary mechanism study showed 1 exerted its anti-liver fibrosis effect by regulating TGF-ß1/Smad2/3 signaling pathway.

New Scabimycins A-C Isolated from Streptomyces acidiscabies (Lu19992).

Peptide natural products displaying a wide range of biological activities have become important drug candidates over the years. Microorganisms have been a powerful source of such bioactive peptides, and Streptomyces have yielded many novel natural products thus far. In an effort to uncover such new, meaningful compounds, the metabolome of Streptomyces acidiscabies was analyzed thoroughly. Three new compounds, scabimycins A-C (1-3), were discovered, and their chemical structures were elucidated by NMR spectroscopy. The relative and absolute configurations were determined using ROESY NMR experiments and advanced Marfey's method.

Multiple strain analysis of Streptomyces species from Philippine marine sediments reveals intraspecies heterogeneity in antibiotic activities.

The marine ecosystem has become the hotspot for finding antibiotic-producing actinomycetes across the globe. Although marine-derived actinomycetes display strain-level genomic and chemodiversity, it is unclear whether functional traits, i.e., antibiotic activity, vary in near-identical Streptomyces species. Here, we report culture-dependent isolation, antibiotic activity, phylogeny, biodiversity, abundance, and distribution of Streptomyces isolated from marine sediments across the west-central Philippines. Out of 2212 marine sediment-derived actinomycete strains isolated from 11 geographical sites, 92 strains exhibited antibacterial activities against multidrug-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. The 16S rRNA and rpoB gene sequence analyses confirmed that antibiotic-producing strains belong to the genus Streptomyces, highlighting Streptomyces parvulus as the most dominant species and three possible new species. Antibiotic-producing Streptomyces strains were highly diverse in Southern Antique, and species diversity increase with marine sediment depth. Multiple strains with near-identical 16S rRNA and rpoB gene sequences displayed varying strength of antibiotic activities. The genotyping of PKS and NRPS genes revealed that closely related antibiotic-producing strains have similar BGC domains supported by their close phylogenetic proximity. These findings collectively suggest Streptomyces' intraspecies adaptive characteristics in distinct ecological niches that resulted in outcompeting other bacteria through differential antibiotic production.

Biosynthesis of the nucleoside antibiotic angustmycins: identification and characterization of the biosynthetic gene cluster reveal unprecedented dehydratase required for exo-glycal formation.

The nucleoside antibiotic angustmycin, produced by some Streptomyces strains, is composed of adenine and C6 sugar and shows antibiotic and antitumor activities. In this study, we propose a biosynthetic pathway for angustmycin using a heterologous expression experiment coupled with in silico analysis of the angustmycin biosynthetic gene (agm) cluster. The biochemical characterization of Agm6 demonstrated its role in angustmycin biosynthesis as an unprecedented dehydratase.

Androgen receptor antagonists produced by Streptomyces overcome resistance to enzalutamide.

Prostate cancer (PC) is a leading cause of cancer-related death in men in Western countries. Androgen receptor (AR) signaling is a major driver of PC; therefore, androgen deprivation by medical and surgical castration is the standard treatment for patients with PC. However, over time, most patients will progress to metastatic castration-resistant PC. Enzalutamide is the only AR antagonist approved by the Food and Drug Administration for the treatment of metastatic castration-resistant PC. However, resistance to enzalutamide also develops in most patients with castration-resistant PC. Thus, there is an urgent need to develop new AR antagonists with new structures. For this purpose, we conducted both in silico and natural product screenings. From the in silico screening, we obtained T5853872 and more potent compound, STK765173. From the natural product screening, the novel compound arabilin was isolated from Streptomyces sp. MK756-CF1. Unlike STK765173, arabilin could overcome resistance to enzalutamide. Furthermore, we also extracted a novel compound, antarlide A, and its geometric isomers from Streptomyces sp. BB47. Antarlides A-F have novel 22-membered-ring macrocyclic structures, while antarlides G and H have 20-membered-ring structures. Both antarlides B and G showed potent AR antagonist activity in prostate cancer cells and could overcome resistance to enzalutamide.

Heat Shock Repressor HspR Directly Controls Avermectin Production, Morphological Development, and H2O2 Stress Response in Streptomyces avermitilis.

The heat shock response (HSR) is a universal cellular response that promotes survival following temperature increase. In filamentous Streptomyces, which accounts for ∼70% of commercial antibiotic production, HSR is regulated by transcriptional repressors; in particular, the widespread MerR-family regulator HspR has been identified as a key repressor. However, functions of HspR in other biological processes are unknown. The present study demonstrates that HspR pleiotropically controls avermectin production, morphological development, and heat shock and H2O2 stress responses in the industrially important species Streptomyces avermitilis. HspR directly activated ave structural genes (aveA1 and aveA2) and H2O2 stress-related genes (katA1, catR, katA3, oxyR, ahpC, and ahpD), whereas it directly repressed heat shock genes (HSGs) (the dnaK1-grpE1-dnaJ1-hspR operon, clpB1p, clpB2p, and lonAp) and developmental genes (wblB, ssgY, and ftsH). HspR interacted with PhoP (response regulator of the widespread PhoPR two-component system) at dnaK1p to corepress the important dnaK1-grpE1-dnaJ1-hspR operon. PhoP exclusively repressed target HSGs (htpG, hsp18_1, and hsp18_2) different from those of HspR (clpB1p, clpB2p, and lonAp). A consensus HspR-binding site, 5'-TTGANBBNNHNNNDSTSHN-3', was identified within HspR target promoter regions, allowing prediction of the HspR regulon involved in broad cellular functions. Taken together, our findings demonstrate a key role of HspR in the coordination of a variety of important biological processes in Streptomyces species. IMPORTANCE Our findings are significant to clarify the molecular mechanisms underlying HspR function in Streptomyces antibiotic production, development, and H2O2 stress responses through direct control of its target genes associated with these biological processes. HspR homologs described to date function as transcriptional repressors but not as activators. The results of the present study demonstrate that HspR acts as a dual repressor/activator. PhoP cross talks with HspR at dnaK1p to coregulate the heat shock response (HSR), but it also has its own specific target heat shock genes (HSGs). The novel role of PhoP in the HSR further demonstrates the importance of this regulator in Streptomyces. Overexpression of hspR strongly enhanced avermectin production in Streptomyces avermitilis wild-type and industrial strains. These findings provide new insights into the regulatory roles and mechanisms of HspR and PhoP and facilitate methods for antibiotic overproduction in Streptomyces species.

Inhibition of Three Potato Pathogens by Phenazine-Producing Pseudomonas spp. Is Associated with Multiple Biocontrol-Related Traits.

Phenazine-producing Pseudomonas spp. are effective biocontrol agents that aggressively colonize the rhizosphere and suppress numerous plant diseases. In this study, we compared the ability of 63 plant-beneficial phenazine-producing Pseudomonas strains representative of the worldwide diversity to inhibit the growth of three major potato pathogens: the oomycete Phytophthora infestans, the Gram-positive bacterium Streptomyces scabies, and the ascomycete Verticillium dahliae. The 63 Pseudomonas strains are distributed among four different subgroups within the P. fluorescens species complex and produce different phenazine compounds, namely, phenazine-1-carboxylic acid (PCA), phenazine-1-carboxamide (PCN), 2-hydroxyphenazine-1-carboxylic acid, and 2-hydroxphenazine. Overall, the 63 strains exhibited contrasted levels of pathogen inhibition. Strains from the P. chlororaphis subgroup inhibited the growth of P. infestans more effectively than strains from the P. fluorescens subgroup. Higher inhibition was not associated with differential levels of phenazine production nor with specific phenazine compounds. The presence of additional biocontrol-related traits found in P. chlororaphis was instead associated with higher P. infestans inhibition. Inhibition of S. scabies by the 63 strains was more variable, with no clear taxonomic segregation pattern. Inhibition values did not correlate with phenazine production nor with specific phenazine compounds. No additional synergistic biocontrol-related traits were found. Against V. dahliae, PCN producers from the P. chlororaphis subgroup and PCA producers from the P. fluorescens subgroup exhibited greater inhibition. Additional biocontrol-related traits potentially involved in V. dahliae inhibition were identified. This study represents a first step toward harnessing the vast genomic diversity of phenazine-producing Pseudomonas spp. to achieve better biological control of potato pathogens. IMPORTANCE Plant-beneficial phenazine-producing Pseudomonas spp. are effective biocontrol agents, thanks to the broad-spectrum antibiotic activity of the phenazine antibiotics they produce. These bacteria have received considerable attention over the last 20 years, but most studies have focused only on the ability of a few genotypes to inhibit the growth of a limited number of plant pathogens. In this study, we investigated the ability of 63 phenazine-producing strains, isolated from a wide diversity of host plants on four continents, to inhibit the growth of three major potato pathogens: Phytophthora infestans, Streptomyces scabies, and Verticillium dahliae. We found that the 63 strains differentially inhibited the three potato pathogens. These differences are in part associated with the nature and the quantity of the phenazine compounds being produced but also with the presence of additional biocontrol-related traits. These results will facilitate the selection of versatile biocontrol agents against pathogens.

Strain Improvement Program of Streptomyces roseosporus for Daptomycin Production.

Daptomycin is a cyclic lipopeptide antibiotic with potent activity against gram-positive bacteria. It has a calcium-dependent mechanism of action that disrupts multiple features of the bacterial membrane function. This antibiotic is highly demanded due to its effectiveness against to microorganisms resistant to other antibiotics, including vancomycin-resistant Staphylococcus aureus (VRSA) and methicillin-resistant S. aureus (MRSA). Daptomycin is produced by fermentation of Streptomyces roseosporus, currently identified as Streptomyces filamentosus. However, low fermentation yields and high production costs are reported. This chapter describes a method of strain improvement involving random mutagenesis, rational screening by bioassay, and flask fermentation. The ultimate objective is to select mutants of S. roseosporus overproducing daptomycin in order to design a more cost-effective daptomycin production.

A metallo-ß-lactamase enzyme for internal detoxification of the antibiotic thienamycin.

Thienamycin, the first representative of carbapenem antibiotics was discovered in the mid-1970s from soil microorganism, Streptomyces cattleya, during the race to discover inhibitors of bacterial peptidoglycan synthesis. Chemically modified into imipenem (N-formimidoyl thienamycin), now one of the most clinically important antibiotics, thienamycin is encoded by a thienamycin gene cluster composed of 22 genes (thnA to thnV) from S. cattleya NRRL 8057 genome. Interestingly, the role of all thn-genes has been experimentally demonstrated in the thienamycin biosynthesis, except thnS, despite its annotation as putative ß-lactamase. Here, we expressed thnS gene and investigated its activities against various substrates. Our analyses revealed that ThnS belonged to the superfamily of metallo-ß-lactamase fold proteins. Compared to known ß-lactamases such as OXA-48 and NDM-1, ThnS exhibited a lower affinity and less efficiency toward penicillin G and cefotaxime, while imipenem is more actively hydrolysed. Moreover, like most MBL fold enzymes, additional enzymatic activities of ThnS were detected such as hydrolysis of ascorbic acid, single strand DNA, and ribosomal RNA. ThnS appears as a MBL enzyme with multiple activities including a specialised ß-lactamase activity toward imipenem. Thus, like toxin/antitoxin systems, the role of thnS gene within the thienamycin gene cluster appears as an antidote against the produced thienamycin.

Resistance-guided isolation and characterization of antibiotic-producing bacteria from river sediments.

BACKGROUND: To tackle the problem of antibiotic resistance, an extensive search for novel antibiotics is one of the top research priorities. Around 60% of the antibiotics used today were obtained from the genus Streptomyces. The river sediments of Bangladesh are still an unexplored source for antibiotic-producing bacteria (APB). This study aimed to isolate novel APB from Padma and Kapotakkho river sediments having the potential to produce antibacterial compounds with known scaffolds by manipulating their self-protection mechanisms. RESULTS: The antibiotic supplemented starch-casein-nitrate agar (SCNA) media were used to isolate antibiotic-resistant APB from the river sediments. The colonies having Streptomyces-like morphology were selectively purified and their antagonistic activity was screened against a range of test bacteria using the cross-streaking method. A notable decrease of the colony-forming units (CFUs) in the antibiotic supplemented SCNA plates compared to control plates (where added antibiotics were absent) was observed. A total of three azithromycin resistant (AZR) and nine meropenem resistant (MPR) isolates were purified and their antagonistic activity was investigated against a series of test bacteria including Shigella brodie, Escherichia coli, Pseudomonas sp., Proteus sp., Staphylococcus aureus, and Bacillus cereus. All the AZR isolates and all but two MPR isolates exhibited moderate to high broad-spectrum activity. Among the isolates, 16S rDNA sequencing of NAr5 and NAr6 were performed to identify them up to species level. The analyses of the sequences revealed that both belong to the genus Streptomyces. CONCLUSIONS: The results from these studies suggest that manipulation of the self-resistance property of APB is an easy and quick method to search for novel APB having the potential to produce potentially novel antibacterial compounds with known scaffolds.

Eliciting the silent lucensomycin biosynthetic pathway in Streptomyces cyanogenus S136 via manipulation of the global regulatory gene adpA.

Actinobacteria are among the most prolific sources of medically and agriculturally important compounds, derived from their biosynthetic gene clusters (BGCs) for specialized (secondary) pathways of metabolism. Genomics witnesses that the majority of actinobacterial BGCs are silent, most likely due to their low or zero transcription. Much effort is put into the search for approaches towards activation of silent BGCs, as this is believed to revitalize the discovery of novel natural products. We hypothesized that the global transcriptional factor AdpA, due to its highly degenerate operator sequence, could be used to upregulate the expression of silent BGCs. Using Streptomyces cyanogenus S136 as a test case, we showed that plasmids expressing either full-length adpA or its DNA-binding domain led to significant changes in the metabolome. These were evident as changes in the accumulation of colored compounds, bioactivity, as well as the emergence of a new pattern of secondary metabolites as revealed by HPLC-ESI-mass spectrometry. We further focused on the most abundant secondary metabolite and identified it as the polyene antibiotic lucensomycin. Finally, we uncovered the entire gene cluster for lucensomycin biosynthesis (lcm), that remained elusive for five decades until now, and outlined an evidence-based scenario for its adpA-mediated activation.

Anti-Infective and Antiviral Activity of Valinomycin and Its Analogues from a Sea Cucumber-Associated Bacterium, Streptomyces sp. SV 21.

The manuscript investigated the isolation, characterization and anti-infective potential of valinomycin (3), streptodepsipeptide P11A (2), streptodepsipeptide P11B (1), and one novel valinomycin analogue, streptodepsipeptide SV21 (4), which were all produced by the Gram-positive strain Streptomycescavourensis SV 21. Although the exact molecular weight and major molecular fragments were recently reported for compound 4, its structure elucidation was not based on compound isolation and spectroscopic techniques. We successfully isolated and elucidated the structure based on the MS2 fragmentation pathways as well as 1H and 13C NMR spectra and found that the previously reported structure of compound 4 differs from our analysis. Our findings showed the importance of isolation and structure elucidation of bacterial compounds in the era of fast omics technologies. The here performed anti-infective assays showed moderate to potent activity against fungi, multi drug resistant (MDR) bacteria and infectivity of the Hepatitis C Virus (HCV). While compounds 2, 3 and 4 revealed potent antiviral activity, the observed minor cytotoxicity needs further investigation. Furthermore, the here performed anti-infective assays disclosed that the symmetry of the valinomycin molecule is most important for its bioactivity, a fact that has not been reported so far.

Discovery of Antibiofilm Activity of Elasnin against Marine Biofilms and Its Application in the Marine Antifouling Coatings.

Biofilms are surface-attached multicellular communities that play critical roles in inducing biofouling and biocorrosion in the marine environment. Given the serious economic losses and problems caused by biofouling and biocorrosion, effective biofilm control strategies are highly sought after. In a screening program of antibiofilm compounds against marine biofilms, we discovered the potent biofilm inhibitory activity of elasnin. Elasnin effectively inhibited the biofilm formation of seven strains of bacteria isolated from marine biofilms. With high productivity, elasnin-based coatings were prepared in an easy and cost-effective way, which exhibited great performance in inhibiting the formation of multi-species biofilms and the attachment of large biofouling organisms in the marine environment. The 16S amplicon analysis and anti-larvae assay revealed that elasnin could prevent biofouling by the indirect impact of changed microbial composition of biofilms and direct inhibitory effect on larval settlement with low toxic effects. These findings indicated the potential application of elasnin in biofilm and biofouling control in the marine environment.

Whole genome sequence of the multi-resistant plant growth-promoting bacteria Streptomyces sp. Z38 with potential application in agroindustry and bio-nanotechnology.

The genus Streptomyces is widely recognized for its biotechnological potential. Due to a need to improve crops, clean up the environment and produce novel antimicrobial molecules exploiting Streptomyces has become a priority. To further explore the biotechnological potential of these organisms we analyzed the genome of the strain Streptomyces sp. Z38 isolated from contaminated roots tissues. Our analysis not only confirmed the ability of the strain to produce plant growth promoting traits but also a range of mechanisms to cope with the toxic effect of heavy metals through genes involved in metal homeostasis and oxidative stress response. The production of silver nanoparticles indicated that Streptomyces sp. Z38 may find utility in Green, Grey and Red biotechnology.

Garcinoic Acids and a Benzophenone Derivative from the Seeds of Garcinia kola and Their Antibacterial Activities against Oral Bacterial Pathogenic Organisms.

In this study, three new garcinoic acid dimers, δ,δ-bigarcinoic acid (1), δ,δ-bi-O-garcinoic acid (2), and γ,δ-bi-O-garcinoic acid (3), and a new benzophenone derivative, (8E)-4-geranyl-3,5-dihydroxybenzophenone (4), as well as seven known compounds (5-11) were isolated from the seeds of Garcinia kola. The structures of the new compounds were elucidated using MALDI-TOF-MS and spectroscopic data, including 1D and 2D NMR and electronic circular dichroism spectra. All of the isolated compounds were evaluated for their antimicrobial activity against two oral pathogens, Porphyromonas gingivalis and Streptococcus sobrinus. Among them, 4 and δ-garcinoic acid (6) exhibited antimicrobial activity against both of these microorganisms (MICs of 31.3-62.5 µM for P. gingivalis and 15.6-31.3 µM for S. sobrinus). These results indicate that some chemical constituents in G. kola seeds have potential application in the prevention of oral diseases.

Genetic analysis of Streptomyces albus J1074 mia mutants suggests complex relationships between post-transcriptional tRNAXXA modifications and physiological traits.

Proteins MiaA and MiaB catalyze sequential isopentenylation and methylthiolation, respectively, of adenosine residue in 37th position of tRNAXXA. The mia mutations were recently shown by us to affect secondary metabolism and morphology of Streptomyces. However, it remained unknown as to whether both or one of the aforementioned modifications is critical for colony development and antibiotic production. Here, we addressed this issue through analysis of Streptomyces albus J1074 strains carrying double miaAmiaB knockout or extra copy of miaB gene. The double mutant differed from wild-type and miaA-minus strains in severity of morphological defects, growth dynamics, and secondary metabolism. Introduction of extra copy of miaB gene into miaA mutant restored aerial mycelium formation to the latter on certain solid media. Hence, miaB gene might be involved in tRNA thiomethylation in the absence of miaA; either MiaA- or MiaB-mediated modification appears to be enough to support normal metabolic and morphological processes in Streptomyces.

Streptomyces sp. 6E3 antimicrobial activity isolated from mineral concentrate. / Actividad antimicrobiana de Streptomyces sp. 6E3 aislado de concentrado de mineral.

The objectives of this study were to determine the antimicrobial activity of a culture of Streptomyces sp. 6E3 isolated from minerals against different pathogenic strains, to produce an extract and to estimate the minimum inhibitory concentration (MIC) of the fractions against methicillin-resistant Staphylococ cus aureus (MRSA). Streptomyces sp. 6E3 showed antimicrobial activity primarily against Staphylococcus aureus (S. aureus). Five of the six fractions presented antimicrobial activity and the most effective gave a MIC of 0.88 ug / mL against S. aureus ATCC 33862, 0.44 ug / mL against S. aureus ATCC 43300 and 1.76 ug / mL vs. a S. aureus MRSA strain. Streptomyces sp. 6E3 has an antimicrobial potential against S. aureus strains resistant to methicillin and non-resistant, being of interest carrying out of more studies on its active metabolites.

El objetivo de este estudio fue determinar la actividad antimicrobiana de un cultivo de Streptomyces sp. 6E3 aislado de minerales frente a diferentes cepas patógenas, producir un extracto y estimar la concen tración mínima inhibitoria (CMI) de las fracciones contra Staphylococcus aureus resistente a meticilina (SARM). La cepa Streptomyces sp. 6E3 mostró actividad antimicrobiana principalmente contra Staphy lococcus aureus (S. aureus). Cinco de las seis fracciones presentaron actividad antimicrobiana y la más efectiva dio una CMI de 0,88 ug/mL frente a S. aureus ATCC 33862, 0,44 ug/mL frente a S. aureus ATCC 43300 y 1,76 ug/mL frente a S. aureus cepa SARM. Streptomyces sp. 6E3 tiene un potencial antimicrobiano frente a cepas de S. aureus resistentes a meticilina y no resistentes, siendo de interés la realización de más estudios sobre sus metabolitos activos.

ß-carboline chemical signals induce reveromycin production through a LuxR family regulator in Streptomyces sp. SN-593.

Actinomycetes bacteria produce diverse bioactive molecules that are useful as drug seeds. To improve their yield, researchers often optimize the fermentation medium. However, exactly how the extracellular chemicals present in the medium activate secondary metabolite gene clusters remains unresolved. BR-1, a ß-carboline compound, was recently identified as a chemical signal that enhanced reveromycin A production in Streptomyces sp. SN-593. Here we show that BR-1 specifically bound to the transcriptional regulator protein RevU in the reveromycin A biosynthetic gene cluster, and enhanced RevU binding to its promoter. RevU belongs to the LuxR family regulator that is widely found in bacteria. Interestingly, BR-1 and its derivatives also enhanced the production of secondary metabolites in other Streptomyces species. Although LuxR-N-acyl homoserine lactone systems have been characterized in Gram-negative bacteria, we revealed LuxR-ß-carboline system in Streptomyces sp. SN-593 for the production of secondary metabolites. This study might aid in understanding hidden chemical communication by ß-carbolines.