Special Issue "Actinomycetes: The Antibiotics Producers"

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (28 February 2018)

Special Issue Editors

Guest Editor
Dr. Evi Stegmann

Department of Microbiology/Biotechnology, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Germany
Website | E-Mail
Interests: antibiotics; glycopeptides; genome mining; metabolic engineering; precursor supply; self-resistance; chelating agent; Amycolatopsis
Guest Editor
Dr. Yvonne Mast

Department of Microbiology/Biotechnology, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Germany
Website | E-Mail
Interests: antibiotics; Streptomycetes; biosynthesis; silent gene cluster; genome mining; genetic engineering; synthetic biology; regulation; overproduction; streptogramins

Special Issue Information

Dear Colleagues,

Actinomycetes are well-known as an inexhaustible source for antibiotics. Most of the identified antimicrobials today have been isolated from the genus Streptomyces, however, not the least, next-generation sequencing techniques, together with genome mining analyses, revealed that there are far more potential antibiotic producers out in nature, also belonging to other genera of the order of Actinomycetales. Some of them have just not been identified because they live in extreme or rare habitats, others have not been made accessible so far due to the impossibility of cultivating them in a lab. Today, around 75 years after Selman Waksman introduced the genus of Streptomyces for the first time, these bacteria still are a treasure chest for the identification of novel antibiotics. This is even more important since new antimicrobials are urgently needed, as resistances of live-threatening pathogenic bacteria are rising. Novel cultivation strategies, elaborated screening techniques, new genetic manipulation tools, more insights in physiological aspects of actinobacterial life style but also knowledge on new secondary metabolite biosynthetic pathways may open up a new era of antibiotic drug discovery. In the Special Issue of “Actinomycetes: The Antibiotics Producers” we will highlight the latest research findings in the field.

Dr. Evi Stegmann
Dr. Yvonne Mast
Guest Editors

Manuscript Submission Information

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Keywords

  • microbiology
  • Streptomyces
  • antibiotics
  • secondary metabolites
  • biosynthesis
  • anti-infectives
  • natural products
  • genetic engineering
  • genome mining
  • isolation
  • cultivation
  • screening
  • biodiversity
  • extreme habitats
  • resistance

Published Papers (17 papers)

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Research

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Open AccessArticle Natural Products from Actinobacteria Associated with Fungus-Growing Termites
Antibiotics 2018, 7(3), 83; https://doi.org/10.3390/antibiotics7030083
Received: 13 August 2018 / Revised: 2 September 2018 / Accepted: 3 September 2018 / Published: 13 September 2018
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Abstract
The chemical analysis of insect-associated Actinobacteria has attracted the interest of natural product chemists in the past years as bacterial-produced metabolites are sought to be crucial for sustaining and protecting the insect host. The objective of our study was to evaluate the phylogeny
[...] Read more.
The chemical analysis of insect-associated Actinobacteria has attracted the interest of natural product chemists in the past years as bacterial-produced metabolites are sought to be crucial for sustaining and protecting the insect host. The objective of our study was to evaluate the phylogeny and bioprospecting of Actinobacteria associated with fungus-growing termites. We characterized 97 Actinobacteria from the gut, exoskeleton, and fungus garden (comb) of the fungus-growing termite Macrotermes natalensis and used two different bioassays to assess their general antimicrobial activity. We selected two strains for chemical analysis and investigated the culture broth of the axenic strains and fungus-actinobacterium co-cultures. From these studies, we identified the previously-reported PKS-derived barceloneic acid A and the PKS-derived rubterolones. Analysis of culture broth yielded a new dichlorinated diketopiperazine derivative and two new tetracyclic lanthipeptides, named rubrominins A and B. The discussed natural products highlight that insect-associated Actinobacteria are highly prolific natural product producers yielding important chemical scaffolds urgently needed for future drug development programs. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessArticle Lysoquinone-TH1, a New Polyphenolic Tridecaketide Produced by Expressing the Lysolipin Minimal PKS II in Streptomyces albus
Antibiotics 2018, 7(3), 53; https://doi.org/10.3390/antibiotics7030053
Received: 4 May 2018 / Revised: 12 June 2018 / Accepted: 22 June 2018 / Published: 28 June 2018
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Abstract
The structural repertoire of bioactive naphthacene quinones is expanded by engineering Streptomyces albus to express the lysolipin minimal polyketide synthase II (PKS II) genes from Streptomyces tendae Tü 4042 (llpD-F) with the corresponding cyclase genes llpCI-CIII. Fermentation of the recombinant
[...] Read more.
The structural repertoire of bioactive naphthacene quinones is expanded by engineering Streptomyces albus to express the lysolipin minimal polyketide synthase II (PKS II) genes from Streptomyces tendae Tü 4042 (llpD-F) with the corresponding cyclase genes llpCI-CIII. Fermentation of the recombinant strain revealed the two new polyaromatic tridecaketides lysoquinone-TH1 (7, identified) and TH2 (8, postulated structure) as engineered congeners of the dodecaketide lysolipin (1). The chemical structure of 7, a benzo[a]naphthacene-8,13-dione, was elucidated by NMR and HR-MS and confirmed by feeding experiments with [1,2-13C2]-labeled acetate. Lysoquinone-TH1 (7) is a pentangular polyphenol and one example of such rare extended polyaromatic systems of the benz[a]napthacene quinone type produced by the expression of a minimal PKS II in combination with cyclases in an artificial system. While the natural product lysolipin (1) has antimicrobial activity in nM-range, lysoquinone-TH1 (7) showed only minor potency as inhibitor of Gram-positive microorganisms. The bioactivity profiling of lysoquinone-TH1 (7) revealed inhibitory activity towards phosphodiesterase 4 (PDE4), an important target for the treatment in human health like asthma or chronic obstructive pulmonary disease (COPD). These results underline the availability of pentangular polyphenolic structural skeletons from biosynthetic engineering in the search of new chemical entities in drug discovery. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessArticle Novel Polyethers from Screening Actinoallomurus spp.
Antibiotics 2018, 7(2), 47; https://doi.org/10.3390/antibiotics7020047
Received: 1 May 2018 / Revised: 12 June 2018 / Accepted: 13 June 2018 / Published: 14 June 2018
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Abstract
In screening for novel antibiotics, an attractive element of novelty can be represented by screening previously underexplored groups of microorganisms. We report the results of screening 200 strains belonging to the actinobacterial genus Actinoallomurus for their production of antibacterial compounds. When grown under
[...] Read more.
In screening for novel antibiotics, an attractive element of novelty can be represented by screening previously underexplored groups of microorganisms. We report the results of screening 200 strains belonging to the actinobacterial genus Actinoallomurus for their production of antibacterial compounds. When grown under just one condition, about half of the strains produced an extract that was able to inhibit growth of Staphylococcus aureus. We report here on the metabolites produced by 37 strains. In addition to previously reported aminocoumarins, lantibiotics and aromatic polyketides, we described two novel and structurally unrelated polyethers, designated α-770 and α-823. While we identified only one producer strain of the former polyether, 10 independent Actinoallomurus isolates were found to produce α-823, with the same molecule as main congener. Remarkably, production of α-823 was associated with a common lineage within Actinoallomurus, which includes A. fulvus and A. amamiensis. All polyether producers were isolated from soil samples collected in tropical parts of the world. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessArticle Specificity of Induction of Glycopeptide Antibiotic Resistance in the Producing Actinomycetes
Antibiotics 2018, 7(2), 36; https://doi.org/10.3390/antibiotics7020036
Received: 28 February 2018 / Revised: 19 April 2018 / Accepted: 20 April 2018 / Published: 25 April 2018
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Abstract
Glycopeptide antibiotics are drugs of last resort for treating severe infections caused by Gram-positive pathogens. It is widely believed that glycopeptide-resistance determinants (van genes) are ultimately derived from the producing actinomycetes. We hereby investigated the relationship between the antimicrobial activity of vancomycin
[...] Read more.
Glycopeptide antibiotics are drugs of last resort for treating severe infections caused by Gram-positive pathogens. It is widely believed that glycopeptide-resistance determinants (van genes) are ultimately derived from the producing actinomycetes. We hereby investigated the relationship between the antimicrobial activity of vancomycin and teicoplanins and their differential ability to induce van gene expression in Actinoplanes teichomyceticus—the producer of teicoplanin—and Nonomuraea gerenzanensis—the producer of the teicoplanin-like A40926. As a control, we used the well-characterized resistance model Streptomyces coelicolor. The enzyme activities of a cytoplasmic-soluble d,d-dipeptidase and of a membrane-associated d,d-carboxypeptidase (corresponding to VanX and VanY respectively) involved in resistant cell wall remodeling were measured in the actinomycetes grown in the presence or absence of subinhibitory concentrations of vancomycin, teicoplanin, and A40926. Results indicated that actinomycetes possess diverse self-resistance mechanisms, and that each of them responds differently to glycopeptide induction. Gene swapping among teicoplanins-producing actinomycetes indicated that cross-talking is possible and provides useful information for predicting the evolution of future resistance gene combinations emerging in pathogens. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessArticle Isolation, Characterization, and Antibacterial Activity of Hard-to-Culture Actinobacteria from Cave Moonmilk Deposits
Antibiotics 2018, 7(2), 28; https://doi.org/10.3390/antibiotics7020028
Received: 26 February 2018 / Revised: 16 March 2018 / Accepted: 19 March 2018 / Published: 22 March 2018
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Abstract
Cave moonmilk deposits host an abundant and diverse actinobacterial population that has a great potential for producing novel natural bioactive compounds. In our previous attempt to isolate culturable moonmilk-dwelling Actinobacteria, only Streptomyces species were recovered, whereas a metagenetic study of the same deposits
[...] Read more.
Cave moonmilk deposits host an abundant and diverse actinobacterial population that has a great potential for producing novel natural bioactive compounds. In our previous attempt to isolate culturable moonmilk-dwelling Actinobacteria, only Streptomyces species were recovered, whereas a metagenetic study of the same deposits revealed a complex actinobacterial community including 46 actinobacterial genera in addition to streptomycetes. In this work, we applied the rehydration-centrifugation method to lessen the occurrence of filamentous species and tested a series of strategies to achieve the isolation of hard-to-culture and rare Actinobacteria from the moonmilk deposits of the cave “Grotte des Collemboles”. From the “tips and tricks” that were tested, separate autoclaving of the components of the International Streptomyces Project (ISP) medium number 5 (ISP5) medium, prolonged incubation time, and dilution of the moonmilk suspension were found to most effectively improve colony forming units. Taxonomic analyses of the 40 isolates revealed new representatives of the Agromyces, Amycolatopsis, Kocuria, Micrococcus, Micromonospora, Nocardia, and Rhodococcus species, as well as additional new streptomycetes. The applied methodologies allowed the isolation of strains associated with both the least and most abundant moonmilk-dwelling actinobacterial operational taxonomic units. Finally, bioactivity screenings revealed that some isolates displayed high antibacterial activities, and genome mining uncovered a strong potential for the production of natural compounds. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessArticle High-Throughput Sequencing Analysis of the Actinobacterial Spatial Diversity in Moonmilk Deposits
Antibiotics 2018, 7(2), 27; https://doi.org/10.3390/antibiotics7020027
Received: 12 February 2018 / Revised: 15 March 2018 / Accepted: 16 March 2018 / Published: 21 March 2018
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Abstract
Moonmilk are cave carbonate deposits that host a rich microbiome, including antibiotic-producing Actinobacteria, making these speleothems appealing for bioprospecting. Here, we investigated the taxonomic profile of the actinobacterial community of three moonmilk deposits of the cave “Grotte des Collemboles” via high-throughput sequencing of
[...] Read more.
Moonmilk are cave carbonate deposits that host a rich microbiome, including antibiotic-producing Actinobacteria, making these speleothems appealing for bioprospecting. Here, we investigated the taxonomic profile of the actinobacterial community of three moonmilk deposits of the cave “Grotte des Collemboles” via high-throughput sequencing of 16S rRNA amplicons. Actinobacteria was the most common phylum after Proteobacteria, ranging from 9% to 23% of the total bacterial population. Next to actinobacterial operational taxonomic units (OTUs) attributed to uncultured organisms at the genus level (~44%), we identified 47 actinobacterial genera with Rhodoccocus (4 OTUs, 17%) and Pseudonocardia (9 OTUs, ~16%) as the most abundant in terms of the absolute number of sequences. Streptomycetes presented the highest diversity (19 OTUs, 3%), with most of the OTUs unlinked to the culturable Streptomyces strains that were previously isolated from the same deposits. Furthermore, 43% of the OTUs were shared between the three studied collection points, while 34% were exclusive to one deposit, indicating that distinct speleothems host their own population, despite their nearby localization. This important spatial diversity suggests that prospecting within different moonmilk deposits should result in the isolation of unique and novel Actinobacteria. These speleothems also host a wide range of non-streptomycetes antibiotic-producing genera, and should therefore be subjected to methodologies for isolating rare Actinobacteria. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessFeature PaperArticle Biosynthesis of Rishirilide B
Antibiotics 2018, 7(1), 20; https://doi.org/10.3390/antibiotics7010020
Received: 14 February 2018 / Revised: 1 March 2018 / Accepted: 1 March 2018 / Published: 7 March 2018
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Abstract
Rishirilide B was isolated from Streptomyces rishiriensis and Streptomyces bottropensis on the basis of its inhibitory activity towards alpha-2-macroglobulin. The biosynthesis of rishirilide B was investigated by feeding experiments with different 13C labelled precursors using the heterologous host Streptomyces albus J1074::cos4 containing
[...] Read more.
Rishirilide B was isolated from Streptomyces rishiriensis and Streptomyces bottropensis on the basis of its inhibitory activity towards alpha-2-macroglobulin. The biosynthesis of rishirilide B was investigated by feeding experiments with different 13C labelled precursors using the heterologous host Streptomyces albus J1074::cos4 containing a cosmid encoding of the gene cluster responsible for rishirilide B production. NMR spectroscopic analysis of labelled compounds demonstrate that the tricyclic backbone of rishirilide B is a polyketide synthesized from nine acetate units. One of the acetate units is decarboxylated to give a methyl group. The origin of the starter unit was determined to be isobutyrate. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessArticle Diversification of Secondary Metabolite Biosynthetic Gene Clusters Coincides with Lineage Divergence in Streptomyces
Antibiotics 2018, 7(1), 12; https://doi.org/10.3390/antibiotics7010012
Received: 11 January 2018 / Revised: 6 February 2018 / Accepted: 7 February 2018 / Published: 13 February 2018
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Abstract
We have identified Streptomyces sister-taxa which share a recent common ancestor and nearly identical small subunit (SSU) rRNA gene sequences, but inhabit distinct geographic ranges demarcated by latitude and have sufficient genomic divergence to represent distinct species. Here, we explore the evolutionary dynamics
[...] Read more.
We have identified Streptomyces sister-taxa which share a recent common ancestor and nearly identical small subunit (SSU) rRNA gene sequences, but inhabit distinct geographic ranges demarcated by latitude and have sufficient genomic divergence to represent distinct species. Here, we explore the evolutionary dynamics of secondary metabolite biosynthetic gene clusters (SMGCs) following lineage divergence of these sister-taxa. These sister-taxa strains contained 310 distinct SMGCs belonging to 22 different gene cluster classes. While there was broad conservation of these 22 gene cluster classes among the genomes analyzed, each individual genome harbored a different number of gene clusters within each class. A total of nine SMGCs were conserved across nearly all strains, but the majority (57%) of SMGCs were strain-specific. We show that while each individual genome has a unique combination of SMGCs, this diversity displays lineage-level modularity. Overall, the northern-derived (NDR) clade had more SMGCs than the southern-derived (SDR) clade (40.7 ± 3.9 and 33.8 ± 3.9, mean and S.D., respectively). This difference in SMGC content corresponded with differences in the number of predicted open reading frames (ORFs) per genome (7775 ± 196 and 7093 ± 205, mean and S.D., respectively) such that the ratio of SMGC:ORF did not differ between sister-taxa genomes. We show that changes in SMGC diversity between the sister-taxa were driven primarily by gene acquisition and deletion events, and these changes were associated with an overall change in genome size which accompanied lineage divergence. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Review

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Open AccessReview Acyltransferases as Tools for Polyketide Synthase Engineering
Antibiotics 2018, 7(3), 62; https://doi.org/10.3390/antibiotics7030062
Received: 2 June 2018 / Revised: 14 July 2018 / Accepted: 16 July 2018 / Published: 18 July 2018
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Abstract
Polyketides belong to the most valuable natural products, including diverse bioactive compounds, such as antibiotics, anticancer drugs, antifungal agents, immunosuppressants and others. Their structures are assembled by polyketide synthases (PKSs). Modular PKSs are composed of modules, which involve sets of domains catalysing the
[...] Read more.
Polyketides belong to the most valuable natural products, including diverse bioactive compounds, such as antibiotics, anticancer drugs, antifungal agents, immunosuppressants and others. Their structures are assembled by polyketide synthases (PKSs). Modular PKSs are composed of modules, which involve sets of domains catalysing the stepwise polyketide biosynthesis. The acyltransferase (AT) domains and their “partners”, the acyl carrier proteins (ACPs), thereby play an essential role. The AT loads the building blocks onto the “substrate acceptor”, the ACP. Thus, the AT dictates which building blocks are incorporated into the polyketide structure. The precursor- and occasionally the ACP-specificity of the ATs differ across the polyketide pathways and therefore, the ATs contribute to the structural diversity within this group of complex natural products. Those features make the AT enzymes one of the most promising tools for manipulation of polyketide assembly lines and generation of new polyketide compounds. However, the AT-based PKS engineering is still not straightforward and thus, rational design of functional PKSs requires detailed understanding of the complex machineries. This review summarizes the attempts of PKS engineering by exploiting the AT attributes for the modification of polyketide structures. The article includes 253 references and covers the most relevant literature published until May 2018. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessReview Production of β-Lactamase Inhibitors by Streptomyces Species
Antibiotics 2018, 7(3), 61; https://doi.org/10.3390/antibiotics7030061
Received: 30 May 2018 / Revised: 7 July 2018 / Accepted: 12 July 2018 / Published: 17 July 2018
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Abstract
β-Lactamase inhibitors have emerged as an effective alternative to reduce the effects of resistance against β-lactam antibiotics. The Streptomyces genus is known for being an exceptional natural source of antimicrobials and β-lactamase inhibitors such as clavulanic acid, which is largely applied in clinical
[...] Read more.
β-Lactamase inhibitors have emerged as an effective alternative to reduce the effects of resistance against β-lactam antibiotics. The Streptomyces genus is known for being an exceptional natural source of antimicrobials and β-lactamase inhibitors such as clavulanic acid, which is largely applied in clinical practice. To protect against the increasing prevalence of multidrug-resistant bacterial strains, new antibiotics and β-lactamase inhibitors need to be discovered and developed. This review will cover an update about the main β-lactamase inhibitors producers belonging to the Streptomyces genus; advanced methods, such as genetic and metabolic engineering, to enhance inhibitor production compared with wild-type strains; and fermentation and purification processes. Moreover, clinical practice and commercial issues are discussed. The commitment of companies and governments to develop innovative strategies and methods to improve the access to new, efficient, and potentially cost-effective microbial products to combat the antimicrobial resistance is also highlighted. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessReview Actinomycetes, an Inexhaustible Source of Naturally Occurring Antibiotics
Antibiotics 2018, 7(2), 45; https://doi.org/10.3390/antibiotics7020045
Received: 17 April 2018 / Revised: 7 May 2018 / Accepted: 23 May 2018 / Published: 24 May 2018
Cited by 1 | PDF Full-text (2484 KB) | HTML Full-text | XML Full-text | Correction
Abstract
Global public health faces a desperate situation, due to the lack of effective antibiotics. Coordinated steps need to be taken, worldwide, to rectify this situation and protect the advances in modern medicine made over the last 100 years. Work at Japan’s Kitasato Institute
[...] Read more.
Global public health faces a desperate situation, due to the lack of effective antibiotics. Coordinated steps need to be taken, worldwide, to rectify this situation and protect the advances in modern medicine made over the last 100 years. Work at Japan’s Kitasato Institute has been in the vanguard of many such advances, and work is being proactively tailored to promote the discovery of urgently needed antimicrobials. Efforts are being concentrated on actinomycetes, the proven source of most modern antibiotics. We devised a novel physicochemical screening mechanism, whereby simple physico-chemical properties, in conjunction with related detection methods, such as LC/MS, LC/UV, and polarity, could be used to identify or predict new compounds in a culture broth, simply by comparing results with existing databases. New compounds are isolated, purified, and their structure determined before being tested for any bioactivity. We used lyophilized actinomycete strains from the Kitasato Microbial Library, most more than 35 years old, and found 330 strains were producers of useful bioactive substances. We also tested organisms found in fresh samples collected in the complex environments from around plant roots, as well as from sediments of mangrove forests and oceans, resulting in the discovery of 36 novel compounds from 11 actinomycete strains. A compound, designated iminimycin, containing an iminium ion in the structure was discovered from the culture broth of Streptomyces griseus OS-3601, which had been stored for a long time as a streptomycin-producing strain. This represented the first iminium ion discovery in actinomycetes. Compounds with a cyclopentadecane skeleton containing 5,6-dihydro-4-hydroxyl-2-pyrone ring and tetrahydrofuran ring, designated mangromicins, were isolated from the culture broth of Lechevalieria aerocolonigenes K10-0216 obtained from sediment in a mangrove forest. These structures are extremely unique among natural compounds. From the same culture broth, new steroid compounds, named K10-0216 KA and KB, and other new compounds having a thiazole and a pyridine ring, named pyrizomicin A and B, were discovered. New substances can be found from actinomycetes that have been exhaustively studied. Novel compounds with different skeletons can be found from a single broth of one strain. The sought after new antibiotics will arise from continued exploitation of the actinomycetes, especially rare actinomycetes. Work on new organisms and samples should be augmented by re-examination of known actinomycetes already in storage. New research should also be carried out on the manipulation of culture media, thereby stimulating actinomycete strains to produce novel chemicals. The establishment of wide-ranging international research collaborations will facilitate and expedite the efficient and timely discovery and provision of bioactive compounds to help maintain and promote advances in global public health. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessReview Concepts and Methods to Access Novel Antibiotics from Actinomycetes
Antibiotics 2018, 7(2), 44; https://doi.org/10.3390/antibiotics7020044
Received: 12 April 2018 / Revised: 14 May 2018 / Accepted: 17 May 2018 / Published: 22 May 2018
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Abstract
Actinomycetes have been proven to be an excellent source of secondary metabolites for more than half a century. Exhibiting various bioactivities, they provide valuable approved drugs in clinical use. Most microorganisms are still untapped in terms of their capacity to produce secondary metabolites,
[...] Read more.
Actinomycetes have been proven to be an excellent source of secondary metabolites for more than half a century. Exhibiting various bioactivities, they provide valuable approved drugs in clinical use. Most microorganisms are still untapped in terms of their capacity to produce secondary metabolites, since only a small fraction can be cultured in the laboratory. Thus, improving cultivation techniques to extend the range of secondary metabolite producers accessible under laboratory conditions is an important first step in prospecting underexplored sources for the isolation of novel antibiotics. Currently uncultured actinobacteria can be made available by bioprospecting extreme or simply habitats other than soil. Furthermore, bioinformatic analysis of genomes reveals most producers to harbour many more biosynthetic gene clusters than compounds identified from any single strain, which translates into a silent biosynthetic potential of the microbial world for the production of yet unknown natural products. This review covers discovery strategies and innovative methods recently employed to access the untapped reservoir of natural products. The focus is the order of actinomycetes although most approaches are similarly applicable to other microbes. Advanced cultivation methods, genomics- and metagenomics-based approaches, as well as modern metabolomics-inspired methods are highlighted to emphasise the interplay of different disciplines to improve access to novel natural products. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessReview Streptomyces Differentiation in Liquid Cultures as a Trigger of Secondary Metabolism
Antibiotics 2018, 7(2), 41; https://doi.org/10.3390/antibiotics7020041
Received: 26 February 2018 / Revised: 9 May 2018 / Accepted: 9 May 2018 / Published: 14 May 2018
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Abstract
Streptomyces is a diverse group of gram-positive microorganisms characterised by a complex developmental cycle. Streptomycetes produce a number of antibiotics and other bioactive compounds used in the clinic. Most screening campaigns looking for new bioactive molecules from actinomycetes have been performed empirically, e.g.,
[...] Read more.
Streptomyces is a diverse group of gram-positive microorganisms characterised by a complex developmental cycle. Streptomycetes produce a number of antibiotics and other bioactive compounds used in the clinic. Most screening campaigns looking for new bioactive molecules from actinomycetes have been performed empirically, e.g., without considering whether the bacteria are growing under the best developmental conditions for secondary metabolite production. These screening campaigns were extremely productive and discovered a number of new bioactive compounds during the so-called “golden age of antibiotics” (until the 1980s). However, at present, there is a worrying bottleneck in drug discovery, and new experimental approaches are needed to improve the screening of natural actinomycetes. Streptomycetes are still the most important natural source of antibiotics and other bioactive compounds. They harbour many cryptic secondary metabolite pathways not expressed under classical laboratory cultures. Here, we review the new strategies that are being explored to overcome current challenges in drug discovery. In particular, we focus on those aimed at improving the differentiation of the antibiotic-producing mycelium stage in the laboratory. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessReview Unraveling Nutritional Regulation of Tacrolimus Biosynthesis in Streptomyces tsukubaensis through omic Approaches
Antibiotics 2018, 7(2), 39; https://doi.org/10.3390/antibiotics7020039
Received: 27 February 2018 / Revised: 23 April 2018 / Accepted: 26 April 2018 / Published: 1 May 2018
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Abstract
Streptomyces tsukubaensis stands out among actinomycetes by its ability to produce the immunosuppressant tacrolimus. Discovered about 30 years ago, this macrolide is widely used as immunosuppressant in current clinics. Other potential applications for the treatment of cancer and as neuroprotective agent have been
[...] Read more.
Streptomyces tsukubaensis stands out among actinomycetes by its ability to produce the immunosuppressant tacrolimus. Discovered about 30 years ago, this macrolide is widely used as immunosuppressant in current clinics. Other potential applications for the treatment of cancer and as neuroprotective agent have been proposed in the last years. In this review we introduce the discovery of S. tsukubaensis and tacrolimus, its biosynthetic pathway and gene cluster (fkb) regulation. We have focused this work on the omic studies performed in this species in order to understand tacrolimus production. Transcriptomics, proteomics and metabolomics have improved our knowledge about the fkb transcriptional regulation and have given important clues about nutritional regulation of tacrolimus production that can be applied to improve production yields. Finally, we address some points of S. tsukubaensis biology that deserve more attention. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessFeature PaperReview The Cellular Mechanisms that Ensure an Efficient Secretion in Streptomyces
Antibiotics 2018, 7(2), 33; https://doi.org/10.3390/antibiotics7020033
Received: 27 February 2018 / Revised: 10 April 2018 / Accepted: 11 April 2018 / Published: 14 April 2018
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Abstract
Gram-positive soil bacteria included in the genus Streptomyces produce a large variety of secondary metabolites in addition to extracellular hydrolytic enzymes. From the industrial and commercial viewpoints, the S. lividans strain has generated greater interest as a host bacterium for the overproduction of
[...] Read more.
Gram-positive soil bacteria included in the genus Streptomyces produce a large variety of secondary metabolites in addition to extracellular hydrolytic enzymes. From the industrial and commercial viewpoints, the S. lividans strain has generated greater interest as a host bacterium for the overproduction of homologous and heterologous hydrolytic enzymes as an industrial application, which has considerably increased scientific interest in the characterization of secretion routes in this bacterium. This review will focus on the secretion machinery in S. lividans. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessReview Complex Regulatory Networks Governing Production of the Glycopeptide A40926
Antibiotics 2018, 7(2), 30; https://doi.org/10.3390/antibiotics7020030
Received: 9 March 2018 / Revised: 29 March 2018 / Accepted: 3 April 2018 / Published: 5 April 2018
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Abstract
Glycopeptides (GPAs) are an important class of antibiotics, with vancomycin and teicoplanin being used in the last 40 years as drugs of last resort to treat infections caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. A few new GPAs have since reached
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Glycopeptides (GPAs) are an important class of antibiotics, with vancomycin and teicoplanin being used in the last 40 years as drugs of last resort to treat infections caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. A few new GPAs have since reached the market. One of them is dalbavancin, a derivative of A40926 produced by the actinomycete Nonomuraea sp. ATCC 39727, recently classified as N. gerenzanensis. This review summarizes what we currently know on the multilevel regulatory processes governing production of the glycopeptide A40926 and the different approaches used to increase antibiotic yields. Some nutrients, e.g., valine, l-glutamine and maltodextrin, and some endogenous proteins, e.g., Dbv3, Dbv4 and RpoBR, have a positive role on A40926 biosynthesis, while other factors, e.g., phosphate, ammonium and Dbv23, have a negative effect. Overall, the results available so far point to a complex regulatory network controlling A40926 in the native producing strain. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessReview Novel Aspects of Polynucleotide Phosphorylase Function in Streptomyces
Antibiotics 2018, 7(1), 25; https://doi.org/10.3390/antibiotics7010025
Received: 14 February 2018 / Revised: 13 March 2018 / Accepted: 16 March 2018 / Published: 18 March 2018
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Abstract
Polynucleotide phosphorylase (PNPase) is a 3′–5′-exoribnuclease that is found in most bacteria and in some eukaryotic organelles. The enzyme plays a key role in RNA decay in these systems. PNPase structure and function have been studied extensively in Escherichia coli, but there
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Polynucleotide phosphorylase (PNPase) is a 3′–5′-exoribnuclease that is found in most bacteria and in some eukaryotic organelles. The enzyme plays a key role in RNA decay in these systems. PNPase structure and function have been studied extensively in Escherichia coli, but there are several important aspects of PNPase function in Streptomyces that differ from what is observed in E. coli and other bacterial genera. This review highlights several of those differences: (1) the organization and expression of the PNPase gene in Streptomyces; (2) the possible function of PNPase as an RNA 3′-polyribonucleotide polymerase in Streptomyces; (3) the function of PNPase as both an exoribonuclease and as an RNA 3′-polyribonucleotide polymerase in Streptomyces; (4) the function of (p)ppGpp as a PNPase effector in Streptomyces. The review concludes with a consideration of a number of unanswered questions regarding the function of Streptomyces PNPase, which can be examined experimentally. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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