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BIOPROSP 2011 : Tromsø
Bioprospecting among the Actinobacteria
of Extreme Environments
Alan T. Bull
School of Biosciences,
University of Kent, Canterbury, UK
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• Bioprospecting – the case for Natural Products
• The case for Actinobacteria
• The case for Systematics
• The case for Prospecting the Extremobiosphere
• Recent Case Studies from our group
• Lessons and Prospects
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Nocardiaceae Mycobacteriaceae
Tsukamurellaceae Dietziaceae
Corynebacteriaceae Segniliparaceae
Actinosynnemataceae Pseudonocardiaceae
Streptomycetaceae Actinospicaceae
Catenulisporaceae Micromonosporaceae
Nakamurellaceae Cryptosporangiaceae
Sporichthyaceae Geodermatophilaceae
Acidothermaceae Frankiaceae
Kineosporiaceae Dermacoccaceae Intrasporangiaceae
Dermatophilaceae Yaniellaceae
Micrococcaceae Brevibacteriaceae
Dermabacteraceae Jonesiaceae
Rarobacteraceae Sanguibacteraceae
Beutenbergiaceae Microbacteriaceae
Promicromonosporaceae Bogoriellaceae
Cellulomonadaceae Streptosporangiaceae
Thermomonosporaceae Nocardiopsaceae
Nocardioidaceae Propionibacteriaceae Actinopolysporaceae
Actinomycetaceae Glycomycetaceae Bifidobacteriaceae
Nitriliruptoraceae Acidimicrobiaceae
Coriobacteriaceae Solirubrobacteraceae
Conexibacteraceae Patulibacteraceae
Thermoleophilaceae Rubrobacteraceae
92 99
97
89
79
50
84
68
62
98
93
98
82
64
68
68
91
97
55
52 68
63
0.02
Bifidobacteriales
Acidimicrobiales Coriobacteriales
Rubrobacterales
Solirubrobacterales
Thermoleophilales
Nitriliruptorales/Euzebyales
Actinomycetales
= Actinomycetes
Corynebacterineae
Pseudonocardineae
Streptomycineae
Catenulisporineae
Micromonosporineae
Frankineae
Kineosporiineae
Micrococcineae
Streptosporangineae
Propionibacterineae
Actinopolysporineae Actinomycineae
Glycomycineae
The Class Actinobacteria
A.T. Bull (2011) Extremophiles Handbook, Springer Tokyo pp 1203-1240
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The case for Actinobacteria: why prioritize for Drug Discovery?
• Size and diversity of the taxon
• Widespread global and environmental dispersal
• Rapid discovery of new taxonomic radiations
• Produce ca. 45% all microbial bioactive chemicals
(~9500)
• Possibly only ca. 10% of actinomycete bioactive
chemicals have been discovered to date.
• Large numbers of biosynthetic gene clusters from
whole genome sequencing.
“Arguably the richest source of small molecule
diversity on the planet”
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The Case for Systematics
Role of taxonomy in bioprospecting
• Enables classification and hence detection and identification
• Predicts metabolic potential – taxonomy as a roadmap to products
• Facilitates dereplication of isolates
• IP protection
But essential to develop
• Quicker, more reliable procedures for describing new taxa – current
methods are laborious and time-consuming
• Wider exploration of taxospace, e.g. deep lineage Actinobacteria
sub-classes
• More sophisticated screening for chemical diversity
How have evolutionary and environmental forces shaped the
distribution of bioactive natural products across microbial
diversity?
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Extract Analysis Organisms
Novel Compound Bioactivity
Dereplication: differentiation
of phenotypically ambiguous
strains (and chemicals) to
facilitate efficient screening
and minimizing cost and time
in sorting large collections.
H I T
Compound Characterization
Compound Evaluation
(ADMET Screening)
L E A D Dereplication filters
Drug Target Screen
Chemistry Positive
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A Guide to Biodiscovery
Extreme Environments → Novel Organisms → Novel Natural Products
“Bacteria dwell in virtually every spot that can sustain
any sort of life. And we have underestimated their
global number because we, as members of a
Kingdom far more restricted in potential habitation,
never appreciated the full range of places that might
be searched.”
Stephen Jay Gould (1996) Planet of the bacteria, Washington Post Horizon.
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The Extremobiosphere
-18C to 121C
pH 0 to 13
P up to 110 MPa
Salinity up to 2.5M NaCl
-Radiation up to 60 Gy h-1
Nutrients down to nM concentrations
Moisture content down to aw 0.75
Deep-seas (>200m) ca. 64% Earth surface
Deep biosphere (deep subterranean, deep submarine)
Cryosphere (permanent) ca. 11% Earth surface
Deserts ca. 15% Earth land surface
• Limits to Growth:
• Extreme Earth Environments:
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Extremophilic/-tolerant Actinobacteria?
• Traditionally viewed as autochthonous members of soil and freshwaters
• Now found increasingly in all extreme environments, often as dominant
populations
Order Sub-order Family
Actinomycetales
Bifidobacteriales
Nitriliruptorales
Corynebacterineae
Frankinease
Micrococcinease
Streptomycineae
Actinopolysporinease
Microbacteriaccae
Micrococcaceae
Streptomycetaceae
Actinopolysporaceae
Nitriliruptoraceae
Acidimicrobiales Actidimicrobineae Acidimicrobiaceae
Coriobacteriales
Rubrobacteriales
Thermoleophilales
Solirubrobacterales
“Rubrobacterineae” Rubrobacteraceae
Thermoleophilaceae
Conexibacteraceae
Patulibacteraceae
Solirubrobacteraceae
A.T. Bull (2011) Extremophiles Handbook
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Extremophilic Actinobacteria
Arthrobacter (pressure)
Catenulispora (acidity)
Kocuria (salinity, low temperature)
Nitriliruptor (salinity, alkalinity)
Rubrobacter (salinity, low temperature, high radiation, low moisture)
Thermoleophilum (high temperature)
Extremotolerant Actinobacteria
Dermacoccus (pressure)
Modestobacter (low moisture, low nutrient, high radiation)
Rhodococcus (low temperature, high radiation, pressure)
Streptomyces (low/high temperature, salinity, low moisture, pressure)
Note: some, not all, members of these genera contain extremophilic/
tolerant organisms.
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Extreme Environments Novel Organisms Novel Natural Products
Hyper-arid deserts
[Atacama]
Polar ecosystems
[Terra Nova Bay,
Antarctica]
Deep-seas
[Mariana Trench]
Our Bioprospecting Grounds
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Recent Deep-Sea Actinomycete Hit Strains Isolated by our Group
Depth (m) Organism Compound
>200 Verrucosispora Abyssomicins
atrop-
Abyssomicin C
Enediyene
Proximicins
2004
2007
2005
2008
>2000 Bathyal Streptomyces
Streptomyces
Caboxamycin
Benzoxacystol
2009
2011
>4000 Abyssal Streptomyces Albidopyrone 2007
>6000 Hadal Micromonospora
Dermacoccus
Dipeptide
Dermacozines
2009
2010
Anti bacterial
Enzyme inhibitor
Anti cancer
Anti protozoal
Signalling (?)
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Proximicins ex. Verrucosispora sp. MG-37: Raune Fjord, Norway 250 m
H.-P. Fiedler et al. (2008) J. Antibiotics 61: 158.
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Caboxamycin ex. Streptomyces sp. NTK 937 Canary Basin 3,814 m
C. Hohmann et al. (2009) J. Antibiotics, 62: 99
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Benzoxacystol ex. Streptomyces sp. NTK935 Canary Basin 3,814m
Micrococcus lylae DSM 20315T (X80750)
Streptomyces cheonanensis JCM 14549T (AY822606)
Streptomyces carpaticus NRRL B-16359T (DQ442494)
Streptomyces thermolineatus DSM 41451T (Z68097)
Streptomyces ribosidificus NBRC 13796T (AB184487)
Streptomyces albus subsp. albus DSM 40313T (AJ621602)
Streptomyces rimosus subsp. rimosus JCM 4667T (AB045883)
Streptomyces sporocinereus NBRC 100766T (AB249933)
Streptomyces morookaensis NBRC 13416T (AB184878)
Streptomyces mashuensis DSM 40221T (X79323)
Streptomyces variegatus LMG 20315T (AJ781371)
Streptomyces rutgersensis subsp. rutgersensis DSM40077T (Z76688)
Streptomyces koyangensis NBRC 100598T (AY079156)
Streptomyces coelicolor DSM 40233T (Z76678) 83
Streptomyces coeruleofuscus NRRL-ISP 5144T (AJ399473)
Streptomyces speibonae ATCC BAA-411T (AF452714)
Streptomyces ambofaciens ATCC 23877T (M27245)
Streptomyces caelestis NRRL 2418T (X80824) 95
67
83
Streptomyces somaliensis DSM 40738T (AJ007403)
Streptomyces mexicanus JCM 12681T (AF441168)
Streptomyces thermodiastaticus DSM 40573T (AB018096) 83
Streptomyces acidiscabies ATCC 49003T (D63865)
Streptomyces galbus DSM 40089T (X79852)
Streptomyces mirabilis DSM 40553T (AY999730)
Streptomyces griseoplanus AS 4.1868T (AY999894)
Streptomyces griseus subsp. griseus NBRC 15744T (AB184699)
Streptomyces rubiginosohelvolus NBRC 12912T (AB184240)
Streptomyces mediolani NBRC 15427T (AB184674)
Streptomyces tanashiensis IFO 12919T (AY999856)
strain NTK935
64
Streptomyces globisporus NRRL B-2872T (EF178686)
100
68
85
96
99
0.1
Biological activity
First benzoxazine inhibitor of
glycogen synthase kinase 3β
(IC50 1.35μM).
Alzheimer’s; Type 2 diabetes
J. Nachtigall et al. (2011) J. Antibiotics, in press.
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The Genus Dermacoccus
Pathom-aree et al. (2006) Int. J. System. Evol. Microbiol. 56: 2303
Dermacoccus profondi MT2.2T (AY894329)
Dermacoccus bathari MT2.1T (AY894328)
Dermacoccus abyssi MT1.1T (AY894323)**
Dermacoccus nishinomiyaensis DSM 20448T (X87757)
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Dermacozines ex. Dermacoccus abyssi: Mariana Trench 10,898m
N.M. Abdel-Mageed et al. (2010) Org. Biomol. Chem. 8: 2352.
Biological activity of A and D
Anti cancer and radical scavenging
Anti-trypanosomal
NOVEL NEW
N
N
CONH2
HNO O
N
N
CONH2
OO O
NH
N
CONH2
O
O
COOCH3
NH
N
CONH2 CONH2
O
N
N
CONH2
O
OH
N
N
CONH2
O
O
OH
OH
N
N
O
HO
NH
N
CONH2
CONH2
Dermacozine A Dermacozine B Dermacozine C Dermacozine D
Dermacozine E Dermacozine F Dermacozine G Dermacozine H
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The Atacama Desert
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B. Gomez-Silva (2010) Astrobio, Santiago
Is there Microbial Life in the Atacama Soils?
Oldest, driest on Earth
Extreme aridity for at least 10-15 My
Very low soil OM (0.02-0.04 mg C g-1)
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Yungay – the Hyper-arid Desert core Gypsum crust Nitrate
Rock desert Salar
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Anti-cancer macrolides
Several novel NPs
Novel aromatic polyketide
Polyene antibiotic
New Streptomyces clade isolated from soil of the Laguna de Chaxa, Salar de Atacama, Chile
Anti-MRSA ansamycins
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Chaxamycins : New Ansamycins produced by Atacama Streptomyces strain C34
Bioactivities
Ansamycin 4: active against
Gram +ve and –ve bacteria
Clinical isolates of MRSA,
MIC 5 < 1μg ml-1 (rifamycin
0.002-0.008 μg ml-1)
Ansamycin 1 (methylated at
C28):
Inhibits intrinsic ATPase of
human chaperone Hsp90
(50% activity of 17-AA
Geldamycin)
M.E. Rateb et al. (2011) J. Org. Chem., submitted
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O
CH3
O
R1
OCH3
OH
H3C
R2
R3
CH3
A: R1 =
R2 = OCH3
R3 = OH
B: R1 =
R2 = H
R3 = OH
C: R1 =
R2 = H
R3 = Hatacamycin A-C
Atacamycins : New Macrolactones produced by Atacama Streptomyces strain C38
Positive antitumor activity against 42 human cell lines but no
pronounced selectivity. Best activity vs. adeno carcinoma (IC50 5.9µM)
and breast carcinoma (IC50 2.7µM).
J Nachtigall et al. (2011), in preparation)
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Novel species of Nonomurea isolated from the Salar de Atacama
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Reporter strain screening of antibiotic mode of action : Atacama Nonomurea sp. JP10
Fatty acid synthesis
RNA synthesis
DNA synthesis
Cell envelop
Cell wall synthesis
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Misconceptions that obstruct natural product search and discovery
1. Microbial systematics is simply stamp collecting.
2. The search for natural product is more stamp
collecting.
3. Natural products have become exhausted.
4. Synthetic compounds provide superior drug
candidates than natural products.
5. Isolation and characterization of natural products is
laborious and slow.
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Natural products from actinomycetes in the extremobiosphere
Compound/Discovered Organism Origin Chemistry Bioactivity
Barbumycin (2010) Streptomyces sp. MS Macrolactone Antitumor
Nocardiopsins (2010) Nocardiopsis sp. MS Macrolides Immuno-suppressive
TP-1161 (2010) Nocardiopsis sp. MSp Thiopeptide Anti-bacterial
J BUR-31 (2010) Streptomyces sp. MSp Thiocidin Cytotoxic
Albidopyrone (2009) Streptomyces sp. DSS -Pyrrone Insulin agonist
Ammosamides (2009) Streptomyces sp. DSS Pyrroloquinoline
alkaloids Cell cycle modulators
Arenamides (2009) Salinispora arenicola MS Depsipeptides NFB inhibitors
Caboxamycin (2009) Streptomyces sp. DSS Benzoxazole Antibacterial
Antitumour
Dermacozines (2009) Dermacoccus abyssi DSS Phenazines Antioxidant
Antitumour
Echinomycin (2009) Streptomyces sp. MS Peptide Antibacterial
Indoxamycins (2009) Streptomycete MS Polyketide Antitumor
Marinosporolides (2009) “Marinispora” sp. MS Macrolides Anti-Candida
Splenocins (2009) Streptomyces sp. MS Lactones Anti-inflammatory
Marineosins (2008) Streptomyces sp. MS Spiroaminals Antitumour
Marinopyrroles (2008) Streptomyces sp. MS Halogenated pyrroles Antibacterial
Pacificanones (2008) Salinispora pacifica MS Polyketides Antitumour
Proximicins (2008) Verrucosispora sp. MS Aminofuran Antitumour
Salinipyrrones (2008) Salinispora pacifica MS Polyketides Antitumour
MS, marine sediment; DSS, deep-sea sediment; MSp, marine sponge
*
*
*
*
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Compound/Discovered Organism Origin Chemistry Bioactivity
Arenicolides (2007) Salinispora arenicola MS Polyketides Antitumour
Lucentamycins (2007) Nocardiopsis
lucentensis MS
Non-ribosomal
peptides Antitumour
Piperazimycins (2007) Streptomyces sp. MS Non-ribosomal
peptides Antitumour
Saliniketals (2007) Salinispora arenicola MS Polyketides Antitumour
Daryamides (2006) Streptomyces sp. MS Polyketides Antitumour
Marinomycins (2006) “Marinispora” sp. MS Polyketides Antitumour
Streptokordin (2006) Streptomyces sp. DSS Methylpyridine Antitumor
Chinikomycins (2005) Streptomyces sp. MS Polyketide Antitumour
Frigocyclinone (2005) Streptomyces griseus AS Angucyclinone Antitumour
Gephyromycin (2005) Streptomyces griseus AS Angucyclinone Glutaminergic
Lipocarbazoles (2005) Tsukamurella sp. DSS Carbazole Antioxidant
Abyssomicins (2004)
[atrop-abyssomicin C] (2007) Verrucosispora maris MS Polycyclic polyketide Antibacterial
Chandrananimycins (2003) Actinomadora sp. MS Phenoxazin Antitumour
Salinosporamide A (2003) Salinispora tropica MS Polyketide/non-
ribosomal peptide Antitumor
MS, marine sediment; DSS, deep-sea sediment; AS, Antarctic soil
*
*
*
*
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PCA analysis of Drugs and Natural Products
R.A. Bauer et al., Curr. Opin. Chem. Biol. 2010, 14: 308
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Actinobacterial Taxospace
A.C. Ward & N. Bora. Curr. Opin. Microbiol. 2006, 9, 279.
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Abyssomicins: History of a Perfect Hit “inspirational natural products” [K.C. Nicolaou]
Source: deep sea sediment 2001
Organism: new actinomycete (Verrucosispora maris) 2004
Product: new chemical entity 2001
Chemistry: family of spirotetronate polyketides
(B, C, D, E, G, H, I)
2004 – 2010
Complete chemical synthesis: discovery of
atrop-abyssomicin C
2005, 2006
Screen: nutrient reversion assay
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Bioactivity: Gram +ve antibacterial including MRSA, VRSA 2004
2007
MIC abyssomicin C: MRSA 4μg ml-1; 20μM
MIC atrop-abyssomicin C: 15μM
Target: p-aminobenzoic acid synthesis, 1st-in-a-class compound 2004
Mode of action: co-valent binding to PabB subunit of 4-amino-4-
deoxychorismate synthase at Cys-263
2007
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Patent filing: Germany, European Union, USA 2003
Pharma discussions: Actelion, AiCuris, Basilea, Cubist, Nereus,
Novartis, Sanofi-Aventis 2004-2008
Other organisms: Streptomyces incl. non-marine 2007-2010
New Targets: Mycobacterium tuberculosis H37Rv (bactericidal, 3.6μM) 2010
A natural product from a region of underexploited chemical space
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?? LESSONS ??
• Missing the stage from detecting a compound and its target to the
next step – checking the in vitro in in vivo assays and determining
the basic toxicity, i.e. Moving from hit to lead. ADMET and other
screens.
• Include medicinal chemistry
• MICs too high? cf. TB drugs (isoniazid 0.29μM)
• You need excellent personal contacts to a pharmaceutical company,
even when it’s a small one
• Pharma personnel often do not have a strong interest to develop a
compound coming from outside.
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WHAT ROLE FOR ACADEMIC GROUPS IN NATURAL PRODUCT DRUG PROSPECTING ?
• Search for new scaffolds in regions of unexplored chemical space
• Be circumspect in adhering too strictly to posited “Rules”
• Do not be discouraged by initially unpromising MICs or IC50s
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Strategies for Accessing Undiscovered Natural Products
• Focus on novel organisms (innovative isolation, e.g.
diffusion chambers, phage indicators)
e.g. deep lineage actinobacteria
• Maximise gene expression (diversity of production
media and conditions)
• Research allelopathic phenomena and allelochemicals
• Metagenomics (analysis and reverse metagenomics of
environmental DNA)
• Whole genome sequencing (screen for biosynthetic
gene clusters)
_____________________________________________
• This is a multidisciplinary game - DON’T WORK ALONE!
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Thanks to: Collecting Expeditions:
Koki Horikoshi [Tokyo]
Doug Masson [Southampton]
Gjert Knutsen [Bergen]
Juan Asenjo [Santiago]
Luis Caceres V. [Antofagasta]
Microbiology/Molecular Biology:
Mike Goodfellow [Newcastle]
Jem Stach [Kent/Newcastle]
Chemistry:
Hans-Peter Fiedler [Tübingen ]
Roderich Süssmuth [Berlin]
Marcel Jaspars [Aberdeen]
ATB supported by: Natural Environment Research Council
UK; Biotechnology & Biosciences Research Council UK;
The Leverhulme Trust; Boehringer Ingelheim; The Royal
Society