Marine Actinomycetes in Biodiscovery 27.2 Genomics and Genome Mining for Discovery of New Antibiotics 665
Part E | 27.2
cal structures and unique biological activities [27.9].
Listed below are some recent examples of bioactive
natural products isolated from marine-sourced actinomycetes exemplifying the diversity of novel structures
and molecular scaffolds.
A new marine actinomycetes genus, Marinospora
(strain CNQ-140) was isolated from a sediment sample at 56 m offshore of La Jolla, California and shown
to contain marinomycin A–D [27.41]. Marinomycin
A was the most potent antibacterial agent showing
in vitro minimum inhibitory concentrations (MIC 90 ) of
0:13 mM against both methicillin-resistant S. aureus
(MRSA) and vancomycin-resistant Enterococcus faecium (VREF).
The marine actinomycetes V. maris, isolated from
sediment collected in the Raune Fjord (Norway) produced the nonribosomal peptide synthetase (NRPS)derived polypeptides proximicin A, B, and C [27.42].
Collection was achieved by box grab at 250 m. 16S
rRNA gene sequencing showed similarity of 99:6% to
the type strain Verrucosispora gifhornensis [27.43]. The
proximicins contain a previously unknown -amino
acid (4-aminofuran-2-carboxylic acid).
The lynamicins were discovered from a Marinispora sp. from sediment collected from Mission Bay,
San Diego. Lynamicins A–E are chlorinated bis-indole pyrroles with broad spectrum activity against
Gram-positive and Gram-negative organisms, in addition to activity against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecium
(VREF) [27.44].
Marinopyrroles A and B are halogenated axially
chiral bispyrroles obtained from culture of a Streptomyces sp. from marine sediment collected near La Jolla,
California. The marinopyrroles were isolated as single
atropo-enantiomers and can be racemized at a higher
temperature. Marinopyrrole A had a MIC 90 of 0:61 mM
and marinopyrrole B had a MIC 90 of 1:1 mM against
methicillin-resistant S. aureus (MRSA) [27.45].
A novel Micromonospora species was isolated
from the marine ascidian Didemnum proliferum and
produced diazepinomicin. Diazepinomicin represents
a unique molecular class with a dibenzodiazepine core
linked to a farnesyl side chain. Diazepinomicin showed
modest activity against Gram-positive bacteria [27.46].
Lipoxazolidinones A, B, and C have been isolated form new marine actinomycetes, Marinospora sp.
from a sediment sample collected in Cocos Lagoon,
Guam. Lipoxazolidinones A had broad spectrum activity against Gram-positive bacteria (MIC values ranging
from 0:5 to 5 mg=mL) and MIC values of 12 mg=mL
against two strains of Haemophilis influenzae. The
antibacterial spectrum and potency were similar to
that of linezolid [27.47]. The lipoxazolidinones are 4oxazolidinones while linezolid has a 2-oxazolidinone
skeleton.
Cyclic meroterpenoid antibiotics merochlorins A–
D have been isolated from a Streptomyces sp. (strain
CNH-189) from a marine sediment sample collected
from Oceanside, California. Merochlorins A and
B showed strong inhibition or several methicillinresistant S. aureus strains with MICs in the range of
24 g=mL [27.48].
Salinosporamide A, containing an unusual -
lactam-ˇ-lactone bicyclic ring structure, was isolated
from S. tropica [27.17]. The compound was shown to
be a reversible inhibitor of the 20S proteasome and entered clinical trials for the treatment of cancer only three
years after its initial publication. Moreover, the entire
supply of salinisporamide A required for the preclinical
developments and clinical trials has been manufactured
by saline fermentation, bypassing the need for total
synthesis [27.21]. Salinisporamide A exemplifies that
marine-sourced actinomycetes have been shown to be
abundant producers of new and novel structural classes
of natural products and as such will continue to be an
attractive resource for the discovery of new therapeutic
agents [27.19].
27.2 Advances in the Field of Biodiscovery: Genomics and Genome
Mining for Discovery of New Antibiotics
The genome sequencing studies of actinomycetes indicate that they possess larger genomes compared to
other bacteria [27.49] and only a fraction of their coding capacity is used for the production of mostly cryptic
secondary metabolites. Additionally, the genes responsible for production of many compounds can be found
in the genomes of nonproducing strains. Their functions are still under investigation to determine whether
these genes are nonfunctional, are not expressed under standard growth conditions or perhaps these genes
require external signalling to turn them on [27.50].
Current techniques may not be powerful enough for
Part E | 27.2
cal structures and unique biological activities [27.9].
Listed below are some recent examples of bioactive
natural products isolated from marine-sourced actinomycetes exemplifying the diversity of novel structures
and molecular scaffolds.
A new marine actinomycetes genus, Marinospora
(strain CNQ-140) was isolated from a sediment sample at 56 m offshore of La Jolla, California and shown
to contain marinomycin A–D [27.41]. Marinomycin
A was the most potent antibacterial agent showing
in vitro minimum inhibitory concentrations (MIC 90 ) of
0:13 mM against both methicillin-resistant S. aureus
(MRSA) and vancomycin-resistant Enterococcus faecium (VREF).
The marine actinomycetes V. maris, isolated from
sediment collected in the Raune Fjord (Norway) produced the nonribosomal peptide synthetase (NRPS)derived polypeptides proximicin A, B, and C [27.42].
Collection was achieved by box grab at 250 m. 16S
rRNA gene sequencing showed similarity of 99:6% to
the type strain Verrucosispora gifhornensis [27.43]. The
proximicins contain a previously unknown -amino
acid (4-aminofuran-2-carboxylic acid).
The lynamicins were discovered from a Marinispora sp. from sediment collected from Mission Bay,
San Diego. Lynamicins A–E are chlorinated bis-indole pyrroles with broad spectrum activity against
Gram-positive and Gram-negative organisms, in addition to activity against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecium
(VREF) [27.44].
Marinopyrroles A and B are halogenated axially
chiral bispyrroles obtained from culture of a Streptomyces sp. from marine sediment collected near La Jolla,
California. The marinopyrroles were isolated as single
atropo-enantiomers and can be racemized at a higher
temperature. Marinopyrrole A had a MIC 90 of 0:61 mM
and marinopyrrole B had a MIC 90 of 1:1 mM against
methicillin-resistant S. aureus (MRSA) [27.45].
A novel Micromonospora species was isolated
from the marine ascidian Didemnum proliferum and
produced diazepinomicin. Diazepinomicin represents
a unique molecular class with a dibenzodiazepine core
linked to a farnesyl side chain. Diazepinomicin showed
modest activity against Gram-positive bacteria [27.46].
Lipoxazolidinones A, B, and C have been isolated form new marine actinomycetes, Marinospora sp.
from a sediment sample collected in Cocos Lagoon,
Guam. Lipoxazolidinones A had broad spectrum activity against Gram-positive bacteria (MIC values ranging
from 0:5 to 5 mg=mL) and MIC values of 12 mg=mL
against two strains of Haemophilis influenzae. The
antibacterial spectrum and potency were similar to
that of linezolid [27.47]. The lipoxazolidinones are 4oxazolidinones while linezolid has a 2-oxazolidinone
skeleton.
Cyclic meroterpenoid antibiotics merochlorins A–
D have been isolated from a Streptomyces sp. (strain
CNH-189) from a marine sediment sample collected
from Oceanside, California. Merochlorins A and
B showed strong inhibition or several methicillinresistant S. aureus strains with MICs in the range of
24 g=mL [27.48].
Salinosporamide A, containing an unusual -
lactam-ˇ-lactone bicyclic ring structure, was isolated
from S. tropica [27.17]. The compound was shown to
be a reversible inhibitor of the 20S proteasome and entered clinical trials for the treatment of cancer only three
years after its initial publication. Moreover, the entire
supply of salinisporamide A required for the preclinical
developments and clinical trials has been manufactured
by saline fermentation, bypassing the need for total
synthesis [27.21]. Salinisporamide A exemplifies that
marine-sourced actinomycetes have been shown to be
abundant producers of new and novel structural classes
of natural products and as such will continue to be an
attractive resource for the discovery of new therapeutic
agents [27.19].
27.2 Advances in the Field of Biodiscovery: Genomics and Genome
Mining for Discovery of New Antibiotics
The genome sequencing studies of actinomycetes indicate that they possess larger genomes compared to
other bacteria [27.49] and only a fraction of their coding capacity is used for the production of mostly cryptic
secondary metabolites. Additionally, the genes responsible for production of many compounds can be found
in the genomes of nonproducing strains. Their functions are still under investigation to determine whether
these genes are nonfunctional, are not expressed under standard growth conditions or perhaps these genes
require external signalling to turn them on [27.50].
Current techniques may not be powerful enough for