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Chapter Titles (Titles link to detailed contents)

1. General introduction to actinomycete biology

2. Growth and preservation of Streptomyces

3. Microscopical methods

4. Specialised biochemical techniques

5. Mutagenesis of Streptomyces by irradiation or chemicals

6. Transposon mutagenesis in Streptomyces

7. In vitro genetic analysis by conjugation and protoplast fusion

8. Preparation and analysis of genomic and plasmid DNA

9. General considerations about gene cloning in Streptomyces

10. Introduction of DNA into Streptomyces

11. Plasmids and their use for gene cloning

12. Streptomyces phages

13. Cloning with phage vectors

14. Gene disruption and gene replacement

15. Reporter systems

16. RNA methods

17. Production and secretion of proteins by Streptomyces

18. Analysing Streptomyces DNA

19. Media, buffers and suppliers

20. Genome maps and genetically marked strains

21. Maps of DNA fragments

22. Maps of plasmids, transposons and phage genomes

Index (3000 entries)

References Each chapter has a comprehensive list of references

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Detailed Contents

Chapter 1 General introduction to actinomycete biology

Taxonomy of Streptomyces

      The genera of actinomycetes

      The genus Streptomyces

Ecology of Streptomyces

Streptomycetes as pathogens

Some physiological features of primary metabolism in streptomycetes

      Carbon sources

      Nitrogen sources

      Amino acid catabolism

      Biosynthesis

      Some physiological novelties

Antibiotic production by Streptomyces

      Streptomycetes as antibiotic producers

      Antibiosis in soil

      Physiology and regulation of antibiotic production

Developmental biology of Streptomyces

The Streptomyces chromosome and its genetic elements

      DNA base composition

      The chromosome

      Plasmids

      Transposable elements

      Phages

      Restriction and modification of Streptomyces DNA

Genetic studies with streptomycetes and their near relatives

      Actinomycetes used for genetical studies

      Genetics and strain improvement for antibiotic and enzyme production

      Safety guidelines for recombinant DNA experiments with Streptomyces
 

Phylogeny of actinomycetes (33KB)
 

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Chapter 2 Growth and preservation of Streptomyces

Selective isolation of streptomycetes

Making a Streptomyces spore suspension

Plating out a Streptomyces spore suspension

Streptomyces cultures on agar

Growth of mycelium on cellophane overlays, nitrocellulose filters or agar

Growth of Streptomyces mycelium in liquid

Growth of Streptomyces for physiological studies

Conditions for spore germination and reproducible exponential growth and antibiotic production by Streptomyces coelicolor

Germination of Streptomyces spores

      Procedure 1

      Procedure 2

Preparation of aerial mycelium and spores separately

      Aerial mycelium

      Spores

Sporulation of Streptomyces in submerged cultures

Preparation of protoplasts from Streptomyces lividans 66 and S. coelicolor A3(2)

Preservation of Streptomyces strains and phages

      Preparation of lyophils

             Alternative I

             Alternative II

      Growing a culture from the lyophil

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Chapter 3 Microscopical methods

Light microscopy

      Cellophane cultures

      Coverslip or slide cultures

      Impression preparations

      Staining for light microscopy

             DAPI Staining of Streptomyces mycelium

            Staining for respiratory activity

            Immunofluorescent staining of Streptomyces mycelium

Electron microscopy

      Electron microscopy of thin sections

            Sectioning of Streptomyces colonies

            Staining thin sections of Streptomyces colonies for glycogen

Spatial visualisation of gene expression

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Chapter 4 Specialised biochemical techniques

Preparation of cell-free extracts from Streptomyces

      Cell-free extracts from mycelium

      Cell-free extracts from spores

            Small-scale cell-free extract from spores

            Large-scale cell-free extract from spores

Preparation of a coupled transcription-translation system from S. lividans

Two-dimensional polyacrylamide gel electrophoresis and its application to Streptomyces proteins

In-vivo radioactive labelling of Streptomyces proteins

      Two-step liquid cultivation and radioactive labelling method for Streptomyces

      Growth and radioactive labelling of Streptomyces on zirconium-silica beads

Detection and assay of S. coelicolor (and S. lividans) antibiotics

      The S. coelicolor antibiotics

            Actinorhodin

             Undecylprodigiosin

            CDA

            Methylenomycin

      S. lividans as an antibiotic producer

      Secondary metabolite production in S. lividans transformants

2d gel of Streptomyces proteins (167KB)

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Chapter 5 Mutagenesis of Streptomyces by irradiation or chemicals

General remarks about mutagenesis

      The optimal amount of mutagenesis

      Expression of mutations

      Spores or mycelium?

      Choice of mutagen

      Precautions

Mutagenesis of Streptomyces spores by ultraviolet light (UV)

Mutagenesis of Streptomyces spores by N-methyl-N-nitro-N-nitrosoguanidine (NTG)

Isolation of specific classes of mutant

      Resistant mutants

      Mutants that have to be isolated by screening

            Auxotrophs

            Other classes of mutants screened by replica plating

            Mutants recognised by visual examination

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Chapter 6 Transposon mutagenesis in Streptomyces

General points about transposon mutagenesis

      Discovery of Streptomyces transposable elements

      Streptomyces transposons suitable for mutagenesis of Streptomyces

      Use of heterologous transposons for mutagenising Streptomyces genes

      Transposon delivery vectors for Streptomyces

      Isolation of independent mutant strains

      Cloning transposon-tagged Streptomyces DNA in E. coli

Tn4556 from S. fradiae

      A. Transposition of Tn4560 from pUC1169 to a chromosomal location

      B. Protocol for inserting Tn4560 into S. coelicolor NF strains

      C. Tn4560 mutagenesis of SCP2* plasmids in S. lividans

      D. Tn4560 mutagenesis of pock-forming SCP2* in S. coelicolor

IS493 from S. lividans 66

      E. Sectoring method for delivering IS493 derivatives using temperature-sensitive plasmids

IS6100 from Mycobacterium fortuitum

      F. Transposon mutagenesis of S. lividans using pSIT151

Tn5493 derived from Tn5

      G. Mutagenising S. lividans using pJOE2577

      H. Alternative method for isolating S. lividans with random insertions of Tn5493

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Chapter 7 In vivo genetic analysis by conjugation and protoplast fusion

The modes of gene exchange in Streptomyces

      Mating

      Protoplast fusion

      Transduction

      Chromosomal recombination by transformation

      Electroporation

The practicalities of making crosses

Quantitative analysis of crosses

      Recombination frequency

      Frequency of plasmid transfer

      Linkage mapping

Establishing a genetic map by the "four-on-four" procedure

      The "classical" way of analysing the results of a "four-on-four" cross

      Analysing the results of a "four-on-four" cross by minimizing multiple crossovers

Mapping a new marker by a single selection

Plate-crosses

Detection of conjugative plasmids by "pock" formation by transconjugants

Protoplast fusion

Fusion of protoplasts of S. coelicolor or S. lividans

      Genetic analysis by protoplast fusion

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Chapter 8 Preparation and analysis of genomic and plasmid DNA

Isolation of genomic DNA

      Discussion of individual steps

A. Kirby mix procedure for the isolation of genomic DNA

      B. Salting out procedure for the isolation of genomic DNA

      C. CTAB procedure for the isolation of genomic DNA

Isolation of CCC plasmid DNA

      Discussion of individual steps

      A. Plasmid isolation by neutral lysis

      B. Standard CsCl-ethidium bromide gradient centrifugation

      C. CsCl density gradient for removing polysaccharides from DNA

      D. Plasmid isolation by alkaline lysis and potassium acetate precipitation

      E. Plasmid isolation by alkaline lysis and phenol precipitation

      F. Plasmid purification using QIAGEN anion exchange column chromatography

      G. Plasmid isolation by the boiling method

      H. Alkaline denaturation of partially purified DNA samples

      I. Purification of samples using ethidium bromide

      J. Acid phenol (pH4) extraction

      K. "Jurassic preps" plasmid purification using guanidine thiocyanate

Standard agarose gel electrophoresis

Pulsed-field gel electrophoresis

      General considerations

      Standard procedure for preparing Streptomyces chromosomal DNA for PFGE

      Phenol wash procedure for preparation of actinomycete DNA for PFGE

      Digestion of DNA with restriction endonucleases in agarose blocks for PFGE

      Loading gels

      Running conditions for PFGE

      Removal of small DNA fragments

Solutions

      Ammonium acetate

      EDTA pH8

      Lithium chloride

      Sodium chloride

      Sodium hydroxide

      Potassium acetate and sodium acetate, 3M

      Tris-HCl buffer

Gel of CCC plasmid DNAs (110KB)
 

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Chapter 9 General considerations about gene cloning in Streptomyces

Features of Streptomyces genes

Restriction-modification and other host factors

Preparation of vector and target DNA

How many clones are required for making a representative gene library?

Choice and use of restriction endonucleases for making gene libraries

Choice of cloning vector

      Vector host-range

      Size of the target DNA

      Integrating vectors

      Low copy number plasmid vectors

      High copy number plasmid vectors

      Plasmid versus phage vectors

      Positive selection vectors

      E. coli vectors containing Streptomyces selection markers

      Using bifunctional vectors that replicate in E. coli and Streptomyces

Selective markers

      Antibiotic resistance

      Counterselectable markers

Ligation conditions

Transformation

Finding the desired clone

      Sib-Selection

      Antibiotic biosynthetic genes

Confirmation of clones

      Does the phenotype depend on the cloned DNA?

      Is the cloned DNA rearranged?

      Is the promoter for a cloned gene present on the cloned DNA?

What if the desired gene cannot be cloned?

Assessing the quality of Streptomyces gene libraries

Storing gene libraries

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Chapter 10 Introduction of DNA into Streptomyces

Methods available

Restriction barriers

Use of single-stranded DNA

Transformation and transfection in Streptomyces

      Polyethylene glycol (PEG)

      Transformation and transfection frequencies

PEG-assisted transformation of Streptomyces protoplasts with plasmid DNA

      Standard procedure

      Rapid small-scale procedure

      Use of denatured DNA for protoplast transformation

      Spot-transformation

      Cosmid transformation

Electroporation of mycelium

Recognition, selection and screening of Streptomyces transformants

      Lethal zygosis reaction (pocks)

      Fertility

      Resistance markers

      Selection of antibiotic-resistant transformants by overlaying or flooding

            Soft agar overlays

            Flooding

      Detection of melanin-producing colonies

      Screening for plasmid DNA

      Colony hybridisation

            Using nitrocellulose filters

            Using Whatman 541 paper

                   Preparation of colony replicas

                   Hybridisation

                   5 end labelling of oligonucleotide probes

            Using Whatman 540 paper

      Use of the Polymerase Chain Reaction (PCR) to identify transformants

Conjugation from E. coli

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Chapter 11 Plasmids and their use for gene cloning

General properties of Streptomyces plasmids and their use for gene cloning

Wild-type plasmids that have been used extensively to construct cloning vectors

      pIJ101

      pJV1

      pSG5

      SCP2

            Higher copy number derivatives of SCP2*

            SCP2* vectors as delivery systems for gene disruptions

      SLP1 and pSAM2

      Other integrating vectors

List of special purpose vectors

      Bifunctional E. coli-Streptomyces plasmids

      oriT (RK2) vectors for conjugation between E. coli and Streptomyces

       cosmid vectors

      Expression vectors

      Vectors with promoterless reporter genes

      Positive selection vectors

      Integrating vectors

      Unstable and temperature-sensitive plasmids useful for gene replacement and transposon delivery

      Vectors without the tsr gene

      Vectors with resistance markers other than the common ones

      Vectors with blue/white selection (lacZ) in E. coli
 

Map of pIJ101 (16KB)
 

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Chapter 12 Streptomyces phages

The relevance of phages to Streptomyces genetics

Occurrence, isolation and storage of Streptomyces phages

      Lytic and temperate phages

      Phages from soil

      Phages from lysogens

      Phages as industrial contaminants

      Streptomyces phage genetics

      In vivo physiological and genetic studies

      Deletion mutants and DNA packaging limitation

      Phage DNA

Uses of wild-type phages in the study of their hosts

      Transduction

      Localised mutagenesis using generalised transduction

      Restriction-modification systems

Storage of Streptomyces phages

Plaque assay of Streptomyces phages

Single-plaque isolation of Streptomyces phages

Preparation of high-titre Streptomyces phage stocks

Isolation of new Streptomyces phages

      Isolation procedure I (direct method)

      Isolation procedure II (specific enrichment)

Selection of potential transducing phages by pyrophosphate resistance

Generalised transduction of S. venezuelae using SV1 phage

Large-scale preparation of Streptomyces phage DNA

Small-scale preparation of Streptomyces phage DNA

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Chapter 13 Cloning with phage vectors

General features of C31 and its vector derivatives

      Shotgun cloning with C31 vectors

      Choice of C31 vectors for mutational cloning

      Choice of C31 vectors for screening by complementation of mutants or acquisition of new capabilities

      Ligation conditions

      Maximising and estimating insert frequency

      Construction and stability of lysogens

      Homogenotisation

      Application of C31 to gene fusions

General features of the C31::xylE vectors

      KC862: a xylE-containing C31 derivative that gives yellow plaques only when carrying inserts with active promoters

      A single copy number promoter-probe vector, KC859

      Vectors for in situ fusions of xylE to chromosomally located transcription units

Other phage-based cloning systems

      Prophage transformation with phage SAt-1 of S. azureus

      Phage-mediated transduction of plasmids

      Vectors based on other Streptomyces phages

      Use of integration functions of Streptomyces phages

Transfection

Transfer of Streptomyces phage DNA onto nitrocellulose filters for "plaque hybridisation"

Preparation of C31 lysogens

      Procedure A

      Procedure B

"Low-tech" method for detecting C31 derivatives containing resistance genes

Use of glkA counterselection to select deletions from, or loss of, C31 prophages

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Chapter 14 Gene disruption and gene replacement

Creating null mutants

      Method (a). Insertional inactivation via a single crossover

      Method (b). Insertional inactivation via double crossing over

      Method (c). Insertional inactivation using an in-frame deletion

Other factors affecting the choice of approach

      Polar effects

      The size of intervals used

      Mutation stability

Method of delivery

      Non-replicating E. coli plasmids

      Temperature-sensitive replicons

      Phage vectors

      Unstable replicons

Dealing with essential genes

Introduction of point mutations and other subtle changes

Counterselection of the delivery vector

"Heterologous" disruptions and replacements

Choice of resistance markers

Selecting for single crossover intermediates during gene replacemen

A practical example of gene disruption

Homogenotisation

            Problems arising from unintended homogenotisation events

            Cloning mutant alleles by homogenotisation

Gene replacements involving whole gene clusters

Mutational analysis of transcription units
 

Gene replacement using Dog counterselection 13KB)
 

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Chapter 15 Reporter systems

Introduction

The problems with lacZ

Choice of vector: plasmid, phage and transposon systems

Antibiotic resistance genes as reporters: neo and cat

The tyrosinase-encoding operon of S. glaucescens as a reporter system

The whiE (spore pigment) major operon as a reporter system

The catechol 2,3-dioxygenase determinant, xylE, a readily quantified reporter gene for Streptomyces

      Detection of xylE expression in situ in colonies

      Detection of xylE expression in C31 plaques

      Assay of catechol 2,3-dioxygenase in cell-free extracts

Use of the Vibrio harveyi luxAB genes as a reporter system

Reporter systems based on EGFP

A reporter gene encoding a thermostable malate dehydrogenase

      Assay of thermostable malate dehydrogenase in cell-free extracts

The ampC (-lactamase) gene as a reporter

The lac (secreted -galactosidase) gene of S. lividans as a reporter for transcription and secretion

The redD gene of S. coelicolor as an easily scorable reporter of transcription in S. coelicolor and S. lividans

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Chapter 16 RNA methods

General precautions when working with RNA

Harvesting Streptomyces cultures for RNA isolation

Isolation of RNA

Isolation of RNA using modified Kirby mix, phenol/chloroform extraction and DNase I treatment

      Isolation of RNA using CsCl gradients

      Isolation of RNA using SDS and hot phenol

Storage of RNA

Assessing the quantity and quality of RNA preparations

      Spectrophotometry

      Agarose gel electrophoresis

High resolution S1 nuclease mapping

      General strategies for making probes for high resolution S1 nuclease mapping

      Notes of caution in probe construction

      Specific activity of the probe

      How much probe to add to each hybridisation reaction

      High resolution S1 nuclease mapping of the 3 ends of transcripts

      Hybridisation solution

      The practicalities of high resolution S1 nuclease mapping

      Controls

      Generating sequencing ladders for high resolution S1 nuclease mapping

      Interpretation of results

Low resolution S1 nuclease mapping

Primer extension mapping

Northern blotting

In vitro transcription

Streptomyces RNA polymerase purification

      Standard purification of Streptomyces RNA polymerase

      Purification of histidine-tagged RNA polymerase

Preparation of DNA-cellulose

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Chapter 17 Production and secretion of proteins by Streptomyces

Transcription initiation

Translation initiation

Signal peptides

Codon usage

Regulated expression systems

Culture conditions

Levels of expression

A selection of plasmids suitable for intracellular expression

Plasmids suitable for secretion

Optimising expression of Streptomyces genes in E. coli

      Changing the codon usage at the 5 end of a coding region

      E. coli vectors that have been used to over-express streptomycete genes

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Chapter 18 Analysing Streptomyces DNA

DNA sequencing

      Alternative and additional Maxam and Gilbert base-specific reactions for sequencing end-labelled DNA

Sequence analysis

      Identifying protein coding regions

            FRAME analysis

            Codon preference

            Hidden Markov model

      Codon usage tables

      Accessing Streptomyces (actinomycete) sequences in the databases

Design of oligonucleotides for use as probes and PCR primers

PCR conditions

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Chapter 19 Media, buffers and suppliers

Agar Media

      Minimal medium (MM)

      Complete medium (CM)

      Hickey-Tresner agar (HT agar)

      R2 Medium

      R2YE Medium

      R5 Medium

      Mannitol soya flour medium (MS)

      Supplemented minimal medium, solid (SMMS)

      MMT

      Difco nutrient agar (DNA)

      Oxoid nutrient agar (ONA)

      Soft nutrient agar (SNA)

      L agar

Liquid media

      Yeast extract-malt extract medium (YEME)

      Tryptone soya broth (TSB)

      Difco nutrient broth (DNB)

      L broth (LB)

      Supplemented liquid minimal medium (SMM)

      Minimal liquid medium (NMMP)

      Labelling medium for Streptomyces

      2 X YT medium

Growth factor supplements

Buffers

      P (protoplast) Buffer

      T (transformation) buffer

      L (lysis) buffer

      TE Buffer

      SM Buffer

      120 × SSC

Addresses of suppliers

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Chapter 20 Genome maps and genetically marked strains

S. coelicolor A3(2)

      Genetic/physical map

      Genetically marked strains

      Genome sequencing project

S. lividans 66

      Genetic/physical map

      Genetically marked strains

Genetic differences between S. coelicolor A3(2) and S. lividans 66

S. griseus

S. ambofaciens

S. rimosus

Plasmids SCP1 and SLP2

Genome map of S. coelicolor (18KB)
 

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Chapter 21 Maps of DNA fragments

Conventions used for the restriction maps

List of restriction endonucleases, recognition sites and isoschizomers (Table)

Lists of genes

Alphabetical list of resistance and indicator genes, and other DNA fragments (Table)

List of genes grouped according to function

      Resistance genes

      Counterselectable markers

      Indicator genes

      Other DNA fragments

Resistance genes grouped according to antibiotic class

      Aminoglycosides

      Bialaphos, phosphinothricin

      Bleomycin, phleomycin

      Chloramphenicol

      Gyrase inhibitors, novobiocin, ciprofloxacin

      Hygromycin

      Macrotetrolides, nonactin, tetranactin

      MLS (macrolide, lincosamide and streptogramin B) resistance

      Puromycin

      Spectinomycin, streptomycin

      Streptothricins

      Tetracyclines

      Thiostrepton and analogues

      Viomycin, capreomycin B

      Other resistances

Antibiotics, antimetabolites, and suppliers (Table)

Maps of DNA fragments

      Resistance genes

      Counterselectable markers

      Indicator genes

      Other DNA fragments

Map of erythromycin resistance gene (7KB)
 

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Chapter 22 Maps of plasmids, transposons and phage genomes

Conventions used for the restriction maps

Lists of all restriction maps

      Phage C31 and its derivatives (Table)

      Integrating plasmids derived from C31 and phage VWB (Table)

      Plasmid maps grouped according to the Streptomyces replicon (Table)

      E. coli plasmids (Table)

      Transposable elements (Table)

Restriction maps

      Phage C31 and its derivatives

      Integrating plasmids derived from C31 and phage VWB

      Plasmid maps grouped according to the Streptomyces replicon

            pIJ101 derivatives

            pRES1 derivatives

            pJV1 derivatives

            pSG5 derivatives

            SCP2* derivatives

            pSAM2 and SLP1 derivatives

      E. coli plasmids

      Transposable elements

            IS117 derivatives

            IS493 derivatives

            Tn4556 derivatives

            Tn5 derivative

Examples of phage maps (10KB)
 

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Index with 3000 entries

Example of index page (15KB)
 

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Order Form
 

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