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Antibiotics
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Mechanism and Regulation of Antibiotic Synthesis in Streptomyces
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Mechanism and Regulation of Antibiotic Synthesis in Streptomyces

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Mechanism and Evolution of Antibiotic Resistance".

Deadline for manuscript submissions: closed (31 July 2019) | Viewed by 42017

Special Issue Editor

Prof. Dr. George H. Jones

E-Mail Website
Guest Editor
Department of Biology, Emory University, Atlanta, GA 30322, USA
Interests: Streptomyces; antibiotic; actinomycin; RNA decay; tRNA nucleotidyltransferase; polynucleotide phosphorylase; (p)ppGpp

Special Issue Information

Dear Colleagues,

Nearly two-thirds of all the antibiotics used in clinical and veterinary medicine are synthesized as natural products by members of the bacterial genus Streptomyces. While the mechanism and regulation of antibiotic synthesis in these organisms have been the subjects of extensive study, there are many details of these processes that remain to be elucidated. For example, the relationships between the various regulatory systems that modulate antibiotic production, transcriptional activators and repressors, RNA polymerase sigma factors, butyrolactones, highly phosphorylated guanine nucleotides, to name a few, have yet to be fully clarified.

In this Special Issue, reviews and original research papers will explore various aspects of the control and biosynthesis of antibiotics in Streptomyces.

Prof. Dr. George H. Jones
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Streptomyces
  • antibiotic
  • biosynthesis
  • regulation
  • biosynthetic pathway
  • secondary metabolism
  • signaling

Published Papers (7 papers)

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Research

Jump to: Review

12 pages, 870 KiB  
Article
A Structural Analysis of the Angucycline-Like Antibiotic Auricin from Streptomyces lavendulae Subsp. Lavendulae CCM 3239 Revealed Its High Similarity to Griseusins
by Maria Matulova, Lubomira Feckova, Renata Novakova, Erik Mingyar, Dominika Csolleiova, Martina Zduriencikova, Jan Sedlak, Vladimir Patoprsty, Vlasta Sasinkova, Iveta Uhliarikova, Beatrica Sevcikova, Bronislava Rezuchova, Dagmar Homerova and Jan Kormanec
Antibiotics 2019, 8(3), 102; https://doi.org/10.3390/antibiotics8030102 - 25 Jul 2019
Cited by 7 | Viewed by 3839
Abstract
We previously identified the aur1 gene cluster in Streptomyces lavendulae subsp. lavendulae CCM 3239 (formerly Streptomyces aureofaciens CCM 3239), which is responsible for the production of the angucycline-like antibiotic auricin (1). Preliminary characterization of 1 revealed that it possesses an aminodeoxyhexose [...] Read more.
We previously identified the aur1 gene cluster in Streptomyces lavendulae subsp. lavendulae CCM 3239 (formerly Streptomyces aureofaciens CCM 3239), which is responsible for the production of the angucycline-like antibiotic auricin (1). Preliminary characterization of 1 revealed that it possesses an aminodeoxyhexose d-forosamine and is active against Gram-positive bacteria. Here we determined the structure of 1, finding that it possesses intriguing structural features, which distinguish it from other known angucyclines. In addition to d-forosamine, compound 1 also contains a unique, highly oxygenated aglycone similar to those of spiroketal pyranonaphthoquinones griseusins. Like several other griseusins, 1 also undergoes methanolysis and displays modest cytotoxicity against several human tumor cell lines. Moreover, the central core of the aur1 cluster is highly similar to the partial gris gene cluster responsible for the biosynthesis of griseusin A and B in both the nature of the encoded proteins and the gene organization. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Antibiotic Synthesis in Streptomyces)
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18 pages, 1755 KiB  
Article
Comparative Transcriptome Analysis of Streptomyces Clavuligerus in Response to Favorable and Restrictive Nutritional Conditions
by Laura Pinilla, León F. Toro, Emma Laing, Juan Fernando Alzate and Rigoberto Ríos-Estepa
Antibiotics 2019, 8(3), 96; https://doi.org/10.3390/antibiotics8030096 - 19 Jul 2019
Cited by 11 | Viewed by 4580
Abstract
Background: Clavulanic acid (CA), a β-lactamase inhibitor, is industrially produced by the fermentation of Streptomyces clavuligerus. The efficiency of CA production is associated with media composition, culture conditions and physiological and genetic strain characteristics. However, the molecular pathways that govern CA regulation [...] Read more.
Background: Clavulanic acid (CA), a β-lactamase inhibitor, is industrially produced by the fermentation of Streptomyces clavuligerus. The efficiency of CA production is associated with media composition, culture conditions and physiological and genetic strain characteristics. However, the molecular pathways that govern CA regulation in S. clavuligerus remain unknown. Methods and Results: Here we used RNA-seq to perform a comparative transcriptome analysis of S. clavuligerus ATCC 27064 wild-type strain grown in both a favorable soybean-based medium and in limited media conditions to further contribute to the understanding of S. clavuligerus metabolism and its regulation. A total of 350 genes were found to be differentially expressed between conditions; 245 genes were up-regulated in favorable conditions compared to unfavorable. Conclusion: The up-regulated expression of many regulatory and biosynthetic CA genes was positively associated with the favorable complex media condition along with pleiotropic regulators, including proteases and some genes whose biological function have not been previously reported. Knowledge from differences between transcriptomes from complex/defined media represents an advance in the understanding of regulatory paths involved in S. clavuligerus’ metabolic response, enabling the rational design of future experiments. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Antibiotic Synthesis in Streptomyces)
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Review

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16 pages, 1088 KiB  
Review
The Application of Ribosome Engineering to Natural Product Discovery and Yield Improvement in Streptomyces
by Saibin Zhu, Yanwen Duan and Yong Huang
Antibiotics 2019, 8(3), 133; https://doi.org/10.3390/antibiotics8030133 - 30 Aug 2019
Cited by 36 | Viewed by 7448
Abstract
Microbial natural product drug discovery and development has entered a new era, driven by microbial genomics and synthetic biology. Genome sequencing has revealed the vast potential to produce valuable secondary metabolites in bacteria and fungi. However, many of the biosynthetic gene clusters are [...] Read more.
Microbial natural product drug discovery and development has entered a new era, driven by microbial genomics and synthetic biology. Genome sequencing has revealed the vast potential to produce valuable secondary metabolites in bacteria and fungi. However, many of the biosynthetic gene clusters are silent under standard fermentation conditions. By rational screening for mutations in bacterial ribosomal proteins or RNA polymerases, ribosome engineering is a versatile approach to obtain mutants with improved titers for microbial product formation or new natural products through activating silent biosynthetic gene clusters. In this review, we discuss the mechanism of ribosome engineering and its application to natural product discovery and yield improvement in Streptomyces. Our analysis suggests that ribosome engineering is a rapid and cost-effective approach and could be adapted to speed up the discovery and development of natural product drug leads in the post-genomic era. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Antibiotic Synthesis in Streptomyces)
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17 pages, 2574 KiB  
Review
Put a Bow on It: Knotted Antibiotics Take Center Stage
by Stephanie Tan, Gaelen Moore and Justin Nodwell
Antibiotics 2019, 8(3), 117; https://doi.org/10.3390/antibiotics8030117 - 11 Aug 2019
Cited by 30 | Viewed by 7513
Abstract
Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large class of natural products produced across all domains of life. The lasso peptides, a subclass of RiPPs with a lasso-like structure, are structurally and functionally unique compared to other known peptide antibiotics in that [...] Read more.
Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large class of natural products produced across all domains of life. The lasso peptides, a subclass of RiPPs with a lasso-like structure, are structurally and functionally unique compared to other known peptide antibiotics in that the linear peptide is literally “tied in a knot” during its post-translational maturation. This underexplored class of peptides brings chemical diversity and unique modes of action to the antibiotic space. To date, eight different lasso peptides have been shown to target three known molecular machines: RNA polymerase, the lipid II precursor in peptidoglycan biosynthesis, and the ClpC1 subunit of the Clp protease involved in protein homeostasis. Here, we discuss the current knowledge on lasso peptide biosynthesis as well as their antibiotic activity, molecular targets, and mechanisms of action. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Antibiotic Synthesis in Streptomyces)
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16 pages, 988 KiB  
Review
Regulation of Geldanamycin Biosynthesis by Cluster-Situated Transcription Factors and the Master Regulator PhoP
by Juan F. Martín, Angelina Ramos and Paloma Liras
Antibiotics 2019, 8(3), 87; https://doi.org/10.3390/antibiotics8030087 - 30 Jun 2019
Cited by 15 | Viewed by 4641
Abstract
Geldanamycin and the closely related herbimycins A, B, and C are benzoquinone-type ansamycins with antitumoral activity. They are produced by Streptomyces hygroscopicus var. geldanus, Streptomyces lydicus and Streptomyces autolyticus among other Streptomyces strains. Geldanamycins interact with the Hsp-90 chaperone, a protein that [...] Read more.
Geldanamycin and the closely related herbimycins A, B, and C are benzoquinone-type ansamycins with antitumoral activity. They are produced by Streptomyces hygroscopicus var. geldanus, Streptomyces lydicus and Streptomyces autolyticus among other Streptomyces strains. Geldanamycins interact with the Hsp-90 chaperone, a protein that has a key role in tumorigenesis of human cells. Geldanamycin is a polyketide antibiotic and the polyketide synthase contain seven modules organized in three geldanamycin synthases genes named gdmAI, gdmAII, and gdmAIII. The loading domain of GdmI activates AHBA, and also related hydroxybenzoic acid derivatives, forming geldanamycin analogues. Three regulatory genes, gdmRI, gdmRII, and gdmRIII were found associated with the geldanamycin gene cluster in S. hygroscopicus strains. GdmRI and GdmRII are LAL-type (large ATP binding regulators of the LuxR family) transcriptional regulators, while GdmRIII belongs to the TetR-family. All three are positive regulators of geldanamycin biosynthesis and are strictly required for expression of the geldanamycin polyketide synthases. In S. autolyticus the gdmRIII regulates geldanamycin biosynthesis and also expression of genes in the elaiophylin gene cluster, an unrelated macrodiolide antibiotic. The biosynthesis of geldanamycin is very sensitive to the inorganic phosphate concentration in the medium. This regulation is exerted through the two components system PhoR-PhoP. The phoRP genes of S. hygroscopicus are linked to phoU encoding a transcriptional modulator. The phoP gene was deleted in S. hygroscopicus var geldanus and the mutant was unable to grow in SPG medium unless supplemented with 5 mM phosphate. Also, the S. hygroscopicus pstS gene involved in the high affinity phosphate transport was cloned, and PhoP binding sequences (PHO boxes), were found upstream of phoU, phoRP, and pstS; the phoRP-phoU sequences were confirmed by EMSA and nuclease footprinting protection assays. The PhoP binding sequence consists of 11 nucleotide direct repeat units that are similar to those found in S. coelicolor Streptomyces avermitilis and other Streptomyces species. The available genetic information provides interesting tools for modification of the biosynthetic and regulatory mechanisms in order to increase geldanamycin production and to obtain new geldanamycin analogues with better antitumor properties. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Antibiotic Synthesis in Streptomyces)
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17 pages, 859 KiB  
Review
Dissolution of the Disparate: Co-ordinate Regulation in Antibiotic Biosynthesis
by Thomas C. McLean, Barrie Wilkinson, Matthew I. Hutchings and Rebecca Devine
Antibiotics 2019, 8(2), 83; https://doi.org/10.3390/antibiotics8020083 - 18 Jun 2019
Cited by 19 | Viewed by 6663
Abstract
Discovering new antibiotics is vital to combat the growing threat of antimicrobial resistance. Most currently used antibiotics originate from the natural products of actinomycete bacteria, particularly Streptomyces species, that were discovered over 60 years ago. However, genome sequencing has revealed that most antibiotic-producing [...] Read more.
Discovering new antibiotics is vital to combat the growing threat of antimicrobial resistance. Most currently used antibiotics originate from the natural products of actinomycete bacteria, particularly Streptomyces species, that were discovered over 60 years ago. However, genome sequencing has revealed that most antibiotic-producing microorganisms encode many more natural products than previously thought. Biosynthesis of these natural products is tightly regulated by global and cluster situated regulators (CSRs), most of which respond to unknown environmental stimuli, and this likely explains why many biosynthetic gene clusters (BGCs) are not expressed under laboratory conditions. One approach towards novel natural product discovery is to awaken these cryptic BGCs by re-wiring the regulatory control mechanism(s). Most CSRs bind intergenic regions of DNA in their own BGC to control compound biosynthesis, but some CSRs can control the biosynthesis of multiple natural products by binding to several different BGCs. These cross-cluster regulators present an opportunity for natural product discovery, as the expression of multiple BGCs can be affected through the manipulation of a single regulator. This review describes examples of these different mechanisms, including specific examples of cross-cluster regulation, and assesses the impact that this knowledge may have on the discovery of novel natural products. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Antibiotic Synthesis in Streptomyces)
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13 pages, 1134 KiB  
Review
The Link between Purine Metabolism and Production of Antibiotics in Streptomyces
by Smitha Sivapragasam and Anne Grove
Antibiotics 2019, 8(2), 76; https://doi.org/10.3390/antibiotics8020076 - 06 Jun 2019
Cited by 21 | Viewed by 6583
Abstract
Stress and starvation causes bacterial cells to activate the stringent response. This results in down-regulation of energy-requiring processes related to growth, as well as an upregulation of genes associated with survival and stress responses. Guanosine tetra- and pentaphosphates (collectively referred to as (p)ppGpp) [...] Read more.
Stress and starvation causes bacterial cells to activate the stringent response. This results in down-regulation of energy-requiring processes related to growth, as well as an upregulation of genes associated with survival and stress responses. Guanosine tetra- and pentaphosphates (collectively referred to as (p)ppGpp) are critical for this process. In Gram-positive bacteria, a main function of (p)ppGpp is to limit cellular levels of GTP, one consequence of which is reduced transcription of genes that require GTP as the initiating nucleotide, such as rRNA genes. In Streptomycetes, the stringent response is also linked to complex morphological differentiation and to production of secondary metabolites, including antibiotics. These processes are also influenced by the second messenger c-di-GMP. Since GTP is a substrate for both (p)ppGpp and c-di-GMP, a finely tuned regulation of cellular GTP levels is required to ensure adequate synthesis of these guanosine derivatives. Here, we discuss mechanisms that operate to control guanosine metabolism and how they impinge on the production of antibiotics in Streptomyces species. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Antibiotic Synthesis in Streptomyces)
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