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Streptomyces are a genus of ubiquitous soil bacteria from which the majority of clinically utilized antibiotics derive 1 . The production of these antibacterial molecules reflects the relentless competition Streptomyces engage in with other bacteria, including other Streptomyces species 1 , 2 . Here we show that in addition to small-molecule antibiotics, Streptomyces produce and secrete antibacterial protein complexes that feature a large, degenerate repeat-containing polymorphic toxin protein. A cryo-electron microscopy structure of these particles reveals an extended stalk topped by a ringed crown comprising the toxin repeats scaffolding five lectin-tipped spokes, which led us to name them umbrella particles. Streptomyces coelicolor encodes three umbrella particles with distinct toxin and lectin composition. Notably, supernatant containing these toxins specifically and potently inhibits the growth of select Streptomyces species from among a diverse collection of bacteria screened. For one target, Streptomyces griseus , inhibition relies on a single toxin and that intoxication manifests as rapid cessation of vegetative hyphal growth. Our data show that Streptomyces umbrella particles mediate competition among vegetative mycelia of related species, a function distinct from small-molecule antibiotics, which are produced at the onset of reproductive growth and act broadly 3 , 4 . Sequence analyses suggest that this role of umbrella particles extends beyond Streptomyces , as we identified umbrella loci in nearly 1,000 species across Actinobacteria. Streptomyces are discovered to produce antibacterial protein complexes that selectively inhibit the hyphal growth of related species, a function distinct from that of the small-molecule antibiotics they are known for.

Thiazolyl peptides are bacterial secondary metabolites that potently inhibit protein synthesis in Gram-positive bacteria and malarial parasites. Recently, our laboratory and others reported that this class of trithiazolyl pyridine-containing natural products is derived from ribosomally synthesized preproteins that undergo a cascade of posttranslational modifications to produce architecturally complex macrocyclic scaffolds. Here, we report the gene cluster responsible for production of the elongation factor Tu (EF-Tu)-targeting 29-member thiazolyl peptide GE37468 from Streptomyces ATCC 55365 and its heterologous expression in the model host Streptomyces lividans. GE37468 harbors an unusual β-methyl-δ-hydroxy-proline residue that may increase conformational rigidity of the macrocycle and impart reduced entropic costs of target binding. Isotope feeding and gene knockout were employed in the engineered S. lividans strain to identify the P450 monooxygenase GetJ as the enzyme involved in posttranslational transformation of isoleucine 8 to β-methyl-δ-hydroxy-proline through a predicted tandem double hydroxylation/cyclization mechanism. Loss of Ile8 oxygenative cyclization or mutation of Ile8 to alanine via preprotein gene replacement resulted in a 4-fold and 2-fold drop in antibiotic activity, respectively. This report of genetic manipulation of a 29-member thiazolyl peptide sets the stage for further genetic examination of structure activity relationships in the EF-Tu targeting class of thiazolyl peptides.

In this present study, a newly isolated strain, Streptomyces sp. NEAE-H, capable of producing high amount of black extracellular melanin pigment on peptone-yeast extract iron agar and identified as Streptomyces glaucescens NEAE-H. Plackett–Burman statistical design was conducted for initial screening of 17 independent (assigned) variables for their significances on melanin pigment production by Streptomyces glaucescens NEAE-H. The most significant factors affecting melanin production are incubation period, protease-peptone and ferric ammonium citrate. The levels of these significant variables and their interaction effects were optimized by using face-centered central composite design. The maximum melanin production (31.650 μg/0.1 ml) and tyrosinase activity (6089.10 U/ml) were achieved in the central point runs under the conditions of incubation period (6 days), protease-peptone (5 g/L) and ferric ammonium citrate (0.5 g/L). Melanin pigment was recovered by acid-treatment. Higher absorption of the purified melanin pigment was observed in the UV region at 250 nm. It appeared to have defined small spheres by scanning electron microscopy imaging. The maximum melanin yield was 350 mg dry wt/L of production medium. In vitro anticancer activity of melanin pigment was assayed against skin cancer cell line using MTT assay. The IC 50 value was 16.34 ± 1.31 μg/ml for melanin and 8.8 ± 0.5 μg/ml for standard 5-fluorouracil.

It has been hypothesized that some antibiotic resistance genes (ARGs) found in pathogenic bacteria derive from antibiotic-producing actinobacteria. Here we provide bioinformatic and experimental evidence supporting this hypothesis. We identify genes in proteobacteria, including some pathogens, that appear to be closely related to actinobacterial ARGs known to confer resistance against clinically important antibiotics. Furthermore, we identify two potential examples of recent horizontal transfer of actinobacterial ARGs to proteobacterial pathogens. Based on this bioinformatic evidence, we propose and experimentally test a ‘carry-back’ mechanism for the transfer, involving conjugative transfer of a carrier sequence from proteobacteria to actinobacteria, recombination of the carrier sequence with the actinobacterial ARG, followed by natural transformation of proteobacteria with the carrier-sandwiched ARG. Our results support the existence of ancient and, possibly, recent transfers of ARGs from antibiotic-producing actinobacteria to proteobacteria, and provide evidence for a defined mechanism. Some antibiotic resistance genes found in pathogenic bacteria might derive from antibiotic-producing actinobacteria. Here, Jiang et al . provide bioinformatic and experimental evidence supporting this hypothesis, and propose a specific mechanism for the transfer of these genes between bacterial phyla.

It has long been thought that the life cycle of Streptomyces bacteria encompasses three developmental stages: vegetative hyphae, aerial hyphae and spores. Here, we show interactions between Streptomyces and fungi trigger a previously unobserved mode of Streptomyces development. We term these Streptomyces cells ‘explorers’, for their ability to adopt a non-branching vegetative hyphal conformation and rapidly transverse solid surfaces. Fungi trigger Streptomyces exploratory growth in part by altering the composition of the growth medium, and Streptomyces explorer cells can communicate this exploratory behaviour to other physically separated streptomycetes using an airborne volatile organic compound (VOC). These results reveal that interkingdom interactions can trigger novel developmental behaviours in bacteria, here, causing Streptomyces to deviate from its classically-defined life cycle. Furthermore, this work provides evidence that VOCs can act as long-range communication signals capable of propagating microbial morphological switches. Soil is home to many bacteria. In fact, soil gets it characteristic ‘earthy’ smell from a common type of soil bacteria known as Streptomyces. Remarkably, Streptomyces are also the original sources of most of the antibiotics that are prescribed by doctors to treat bacterial infections. Scientists have been studying Streptomyces for over 70 years, and in all this time, there has been unanimous agreement on how these bacteria grow. That is to say that, unlike most other bacteria, Streptomyces grow like plants: they don’t move, and instead produce spores that are dispersed like seeds. This stationary lifestyle makes these bacteria somewhat vulnerable to predators, and so it is thought that Streptomyces make antibiotics to help protect themselves from other bacteria that are able to move around in the soil. However, this established view of Streptomyces growth has now been turned on its head because Jones et al. have discovered that Streptomyces bacteria can indeed move when grown in the presence of fungi. Specifically, when a species of Streptomyces is grown with yeast, some of the bacteria start to explore their environment, move over top of other bacteria and up hard surfaces to heights that would be the equivalent of humans scaling Mount Everest. Unexpectedly, Jones et al. also found that these “explorer” Steptomyces can communicate with nearby Streptomyces bacteria with a perfume-like airborne signal and convince their relatives to begin exploring too. Furthermore, while this volatile signal promotes the growth of Streptomyces, it adversely affects other bacteria and makes them sicker such that they are less able to grow and survive. Together these findings reveal new ways that bacteria and other microbes can interact and communicate with each other. They also emphasise that researchers will need to consider such long-range communication strategies if they hope to better understand microbial communities.

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.

Background The bacterial evolution and the emergence of new species are likely influenced by multiple forces, including long-term environmental pressure such as living in extreme conditions. In this study, the genomes of two potentially new Streptomyces species isolated from a former mine heap in Tarnowskie Góry in Poland, were analyzed. Results A bioinformatic approach revealed notable phylogenetic and metabolic differences between the studied Streptomyces strains, despite originating from the same environment. While both strains are characterized by genetic features common to actinomycetes, additional unique biosynthetic gene clusters were also predicted in their genomes. The comparative genomic analysis with other Streptomyces spp. revealed a high conservation in heavy metal adaptive mechanisms, indicating a preadaptation to extreme conditions. The difference observed in the cad and mer operons could be attributed to the specific adaptations to heavy metal contamination. The high metal tolerance of examined strains was also confirmed by an agar dilution assay in the presence of several heavy metals. The confirmed siderophore production represents an additional mechanism allowing streptomycetes to survive in extreme conditions. On the other hand, both of studied genomes show significant differences in energy acquisition processes and the production of putative novel secondary metabolites. The isolates showed these differences not only among themselves but also compared to other Streptomyces species, indicating their uniqueness. Conclusions Our results demonstrate that extreme environmental conditions can lead to the development of various adaptation mechanisms in the Streptomyces spp. Furthermore, the results indicate that diverse Streptomyces species have developed conserved adaptation mechanisms against the heavy metals under extreme conditions, indicating the emergence of preadaptations that allow bacteria to respond rapidly to polluted environments and evolve their genomes accordingly up to the evolution of new species.

The lincoamide antibiotic lincomycin, derived from Streptomyces lincolnensis , is widely used for the treatment of infections caused by gram-positive bacteria. As a common global regulatory factor of GntR family, DasR usually exists as a regulatory factor that negatively regulates antibiotic synthesis in Streptomyces . However, the regulatory effect of DasR on lincomycin biosynthesis in S. lincolnensis has not been thoroughly investigated. The present study demonstrates that DasR functions as a positive regulator of lincomycin biosynthesis in S. lincolnensis , and its overexpression strain OdasR exhibits a remarkable 7.97-fold increase in lincomycin production compared to the wild-type strain. The effects of DasR overexpression could be attenuated by the addition of GlcNAc in the medium in S. lincolnensis . Combined with transcriptome sequencing and RT-qPCR results, it was found that most structural genes in GlcNAc metabolism and central carbon metabolism were up-regulated, but the lincomycin biosynthetic gene cluster ( lmb ) were down-regulated after dasR knock-out. However, DasR binding were detected with the DasR responsive elements ( dre ) of genes involved in GlcNAc metabolism pathway through electrophoretic mobility shift assay, while they were not observed in the lmb . These findings will provide novel insights for the genetic manipulation of S. lincolnensis to enhance lincomycin production. Key points • DasR is a positive regulator that promotes lincomycin synthesis and does not affect spore production • DasR promotes lincomycin production through indirect regulation • DasR correlates with nutrient perception in S. lincolnensis

As Streptomycetes might produce melanin to survive in stressful environmental conditions, like under metal exposure, supplementing metal ions to the growth medium could be a wise strategy for boosting the production of the pigment. The aim of this study was to test, for the first time, the possibility of boosting S. nashvillensis DSM40314 melanin biosynthesis by adding to the growth medium singularly or, at the same time, different concentrations (1.0, 1.5, and 2.0 g∙L−1) of CuSO4 or/and Fe2(SO4)3. A maximum melanin production of 4.0 ± 0.1 g·L−1 was obtained in shake flasks with a 2.0 g∙L−1 coupled addition of the two metals, while the extracellular tyrosinase activities ranged values between 5.4 and 11.6 ± 0.1 U·L−1. The pigments produced in different conditions were precipitated from the broth supernatants under acidic conditions, purified, and characterized by UV-VIS, FT-IR, and NMR analyses that determined structures like eumelanin pigments. Fermentation experiments in stirred tank reactors allowed to scale up the process in more controlled conditions, further boosting the pigment production up to 4.9 ± 0.1 g·L−1, with an increase of about 22.0% compared to the results obtained in shake flasks.

Microbial resistance to antibiotics currently spans all known classes of natural and synthetic compounds. It has not only hindered our treatment of infections but also dramatically reshaped drug discovery, yet its origins have not been systematically studied. Soil-dwelling bacteria produce and encounter a myriad of antibiotics, evolving corresponding sensing and evading strategies. They are a reservoir of resistance determinants that can be mobilized into the microbial community. Study of this reservoir could provide an early warning system for future clinically relevant antibiotic resistance mechanisms.