Streptomyces griseus

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ever reported from a bacterium, comes from strains of *S. griseus.* Recently, the whole genome sequence of one of its
strains had been completed.

**Description and**
significance

*Streptomyces griseus* are **gram** **positive, aerobic,**
filamentous bacteria**. *Streptomyces griseus* is a**
soil-dwelling bacteria like most of the other species in its genus. S. griseus’
optimal temperature to live in is at 25-35C. The genus *Streptomyces* are
also responsible for the “earthy” smell of soil and the fertility of the soil.
(3) *Streptomyces griseus* produces many useful secondary
metabolites such as enzyme inhibitors and contribute 70% of naturally-occurring
antibiotics. Having *S. griseus’* geome sequenced will
contribute to further discoveries such as its production of anticancer
secondary metabolites.(11) Cultures of Streptomyces griseus can be put into
four categories: “1. those that produce streptomycin 2. those that produce
grisein 3. those that form an antibiotic that is neither streptomycin or
grisein. 4. those that do not form any antibiotic.”(2)

The first person to isolate *Steptomyces griseus* was
Krainsky in 1914 during the outbreak of World War I from Russian soil.(2) In
1915, Dr. Selman A. Waksman, a microbiologist at the Agricultural Department of
Rutgers University, along with an assistant were studying actinomycetes when
they isolated from New Jersey soil, a strain in which they called *Actinomyces*
griseus.*(3) Dr. Waksman was studying how certain substances enabled soil*
microbes to destroy each other and Streptomyces, he found was able to survive
in the soil even under unfavorable conditions. In 1943, *Actinomyces*
griseus*was changed to*Streptomycin griseus.*That*
same year, Albrez Schatz, an assistant of Dr. Waksman, isolated two Actinomyces
strains which proved to be identical to the strain discovered in 1915, yet
somehow these two new strains had antibiotic behavior. Dr. Waksman named this
antibiotic “streptomycin.” It was later determined that the *S. griseus* strain
that gave rise to the antibiotic was able to produce two variants, one in which
had antibiotic activity and had no antibiotic activity. Waksman along with
Schatz and Bugie, found streptomycin to be particularly effective against the
tuberculosis bacteria, *tubercle bacillus.* Feldman and Hinshaw,
two physicians from the Mayo Clinic in Rochester, studied streptomycin’s effect
in guinea pigs with tuberculosis and eventually in human tuberculosis. Feldman
and Hinshaw found streptomycin to be effective in curing two extreme classes of
tuberculosis: tuberculous meningitis and military tuberculosis. (2) In 1952,
Dr. Selman Waksman was awarded the Nobel Prize in Physiology or Medicine for
his discovery of streptomycin as the first antibiotic effective against
tuberculosis. (3)

### Cell structure and metabolism

*S. griseus* has a thick peptidoglycan layer and
lipids stretching its cell wall making it a permeability barrier. When *S.*
griseus*was treated with lysozyme for six hours, the cells did not die*
and was still able to grow. This shows that lysozyme was not able to reach the
murein. ll-Diaminopimelic acid is an important part of the murein in *S.*
griseus*and can be a defining factor in determining similarities with*
other bacteria. In the cell wall of *S. griseus* there is a wide
water filled channel that contains a binding site for the antibiotic streptomycin.
The cell wall of *S. griseus* has a lower density than the
cytoplasmic membrane. (7)

The life cycle of *Streptomyces griseus* courtesy of
Sueharu Horinouchi, University of Tokyo

*S. griseus* have a substrate and an aerial
mycelium. The aerial mycelium has modes of branching that eventually leads
these hyphae to form chains of spores called arthrospores. (1) The A-factor
involved in secondary metabolism and morphological differentiation is also
responsible in triggering the formation of aerial mycelium. When less than 5
µmol of cAMP was added to a disc containing *S. griseus,* there
was rapid aerial mycelium formation however, any amount greater than 5 µmol of
cAMP will inhibit this activity. This evidence suggests that cAMP might be part
of a regulatory pathway to control physiological functions. (8)

The preferred carbon source for *S. griseus’* production of
streptomycin and for growth are as follows in order of preference :
glucose, mannose, starch, dextrin and mannitol. L-asparagine and L-histidine
are good sources of nitrogen for the production of Candicidin, an antibiotic
that *S. griseus* also produces found to be effective against
Candida infections. Potassium, phosphate-phosphorous, sulfate-sulfur, zinc and
iron are also essential for the production of Candicidin. (9) *Streptomyces*
griseus*can obtain its nitrogen from both organic and inorganic*
sources.

*S. griseus’* life cycle is very complex. Their lifecycle comes to
completion with spore formation. *S. griseus* sporulates very
well when placed in liquid culture. (11) They can form endospores when nutrients
are low. (1)

### Ecology

Since *S. griseus* are gram positive
bacteria, their filamentous mycelia are close enough to each other that the
two *S. griseus* are able to communicate. (4) The ability to
signal between the two physically separate *S. griseus* bacteria
in the same mycelium can be attributed to hormonal regulation. *S.*
griseus*along with other species in their genus have an A-factor that*
stimulates streptomycin production and aerial mycelium formation. A-factor
homologues that have a γ-butyrolactone structure have receptors that are highly
specific to aid in discriminating signals received from neighboring organism
thus allowing the cell to recognize the neighbor as a member of its own species
or not. This system is also useful in the survival of in the ecosystem because
A-factor produced by a cell is received by several hyphae and can result in
rapid sporulation of whole populations. (4) The A-factor and its receptor
system acts as a crucial switch for physiological and morphological
differentiation.

*Streptomyces’* varied metabolism allows them to break down insoluble
remains of other organisms and compounds including compounds such as chitin and
lignocellulose. (1)

### Pathology

From current research, *S. griseus* does not
cause any disease. (1)Though *S. griseus* can produce useful
antibiotic, they also have strains that produces toxin. One of these toxin is Valinomycin,
an ionophore that carries K+, was found in indoor air and dust. Valinomycin can
cause apoptosis in NK cells and mitochondrial swelling in peripheral blood
lymphocytes. (12) Some side effects of Valinomycin can include hearing lost,
renal toxicity and dizziness.(16)

### Genome structure

*Streptomyces griseus’* genome sequence consists
of a total of 8, 545, 929 base pairs. (4) *S. griseus’* contain
very large linear chromosomes. *S. griseus* have a very high GC
content that make up about 70%-74% of their DNA. It is hard to construct a map
of *S. griseus’* chromosomes because of their genetic
instability. *Streptomyces* in general, undergoes DNA
rearrangements such as amplification and deletion especially at their
extremities. (11) The genome of *S. griseus* is currently being
sequenced by the University of Tokyo. Plasmids from *S. griseus* are
very ideal to use because of the diverse metabolism of *S. griseus* and
the potential for them to be used as cloning vectors in genetic manipulation.
pSG1 is a 16.6 kb long plasmid in S. griseus that can exist in two maintenance
states: as a free plasmid or used in an integrated sequence.(13) The importance
of pSG1 is still unclear.

### Application to Biotechnology

Besides the obvious antibiotic that *S. griseus* produces
(streptomycin), *S. griseus* also produces many more antibiotics
and useful enzymes. FDM A, an antitumor antibiotic is also derived from gene
clusters of *S. griseus.* FDM A, besides being effective against
P388 mouse leukemia, is able to form a stabled oxidized free radical when
exposed to oxygen contributing to its cytotoxicity characteristic. Recent
research indicates that FDM A might be an effective irreversible inhibitor
against peptidyl-prolyl cis-trans isomerase (PIP) one of which is Pin1 shown to
be an important regulator of the tumor suppressor p53 when DNA is damaged. This
discovery hints to FDM A as a new candidate for anticancer research. (6)

*S. griseus* also secretes different types of hydrolytic
enzymes. *S. griseus* serves as a source of a commercial enzyme
preparation known as Pronase. Pronase has some proteolytic activity. From this
Pronases, chymotrypsin like serine protease can be isolated, one of which is
named S. griseus protease C. (SGPC) (15)

### Current Research

*Streptomyces griseus* was recently found to
produce odor-active metabolites and compounds that give the off-flavor in apple
juice when it is spoiled. The presence of *S. griseus* in soil
gives it its property to spoil water and various foods. *S. griseus’* growth
rate was also shown to be limited when lower oxygen was supplied; however,
there was still sufficient growth of cells to cause spoilage. Of the thirteen
odor-active metabolites of *S. griseus,* only four was shown to
give apple juice the off-flavor when it is spoiled. *Alicyclobacillus*
acidoterrestris*was also studied as a spoilage bacterium. Both*
bacteria were tested together to see how contamination of both strains will
effect off-flavor formation. It is expected to see that *A.*
acidoterrestris’*growth will be reduced because of*S. griseus’*antibiotic*
properties; however, *S. griseus’* growth was also limited. This
result was probably due to competition between the two bacteria for nutrient.
Further research needs to be done to determine the potent odorants and also the
concentration needed to reach the threshold of where S. griseus can detected.
(10)

It is been recently discovered that the γ-butyrolactone synthase and its
receptors involved in the secondary metabolism regulation pathway might have
changed due to evolution. It is seen that the γ-butyrolactone synthase in *S.*
griseus*is more closely related to*Streptomyces coelicolor*and*
that the γ-butyrolactone receptor is more closely related to *Streptomyces*
virginiae.*The γ-butyrolactone receptor is also to believe to exist*
before its synthase counterpart. The γ-butyrolactone synthase and
γ-butyrolactone receptor homologs might have been transferred by plasmids
because the filamentous mycelia of the S. griseus might have allowed the
existence of a diffusible γ-butyrolactone regulatory system. Further research
is needed to see if the specific γ-butyrolactone synthase and γ-butyrolactone
receptor system is needed for survival in the environment for S. griseus and
whether the combination of their homologs acts as method to create
diversity.(14)

Recent research has found that the rare earth, scandium could cause
overproduction of antibiotics in the genus *Streptomyces.* Scandium
causes overproduction of streptomycin when adjusted to the right amount.
Scandium when introduced to *S. griseus* will inhibit its
growth, however, when cultured on SPY medium with more than 5mM of MgSO4,
scandium can cause increase in production of streptomycin on the medium. Scandium
is being investigated to see if it acts on the ribosome and if it somehow
regulates the ribosome’s activity.

### References

[NCBI genome project entrez] [2]

[2.Waksman, S. A., Reilly, H. C., and Harris, Dale A.
“Streptomyces griseus(Krainsky) Waksman and Henrici.” Journal Bacteriology.
1948. Volume 56, p.259-269] [3]

[3. Nobel Prize Presentation Speech] [4]

[4.Horinouchi, S. “Mining and Polishing of the Treasure
Trove in the Bacterial Genus Streptomyces.” Bioscience, Biotechnology, and
Biochemistry. 2007. Volume 71. p.283-299 ] [5]

[5.Keiichi Kawai, Guojun Wang, Susumu Okamoto, Kozo Ochi
(2007) ”The rare earth, scandium, causes antibiotic overproduction in
Streptomyces spp.” FEMS Microbiology Letters. 2007. Volume 274. p.
311–315.] [6]

[6.Wendt-Pienkowski, E., Huang, Y., Zhang, J., Li, B.,
Jiang, H., Kwon, H., Hutchinson, C.R., and Shen, B. “Cloning, Sequencing,
Analysis, and Heterologous Expression of the Fredericamycin Biosynthetic Gene
Cluster from Streptomyces griseus” Journal of the American Chemical Society.
2005. Volume 127. p. 16442 -16452] [7]

[7. Kim, B.H., Andersen, C., Benz, R. “Identification of a
cell wall channel of Streptomyces griseus: the channel contains a binding site
for streptomycin.” Molecular Microbiology. 2001. Volume 41, p.665–673.] [8]

[8.Kang, D-K., Li, X-M., Ochi, K., Horinouchi, S. “Possible
involvement of cAMP in aerial mycelium formation and secondary metabolism in
Streptomyces griseus” Microbiology. 1999. Volume 145. p. 1161-1172.] [9]

[9. Acker, R., Lechevalier, H. “Some Nutritional
Requirements of Streptomyces griseus 3570 for Growth and Candicidin Production”
Applied Microbiology. 1954. Volume 2. p. 152-157. ] [10]

[10. Siegmund, B., Pollinger-Zierler, B. “Growth behavior of
off-flavor-forming microorganisms in apple juice.” Journal of agricultural and
food chemistry. 2007. Volume 55. p.6692-6699.] [11]

[11. Lezhava, Z., Mizukami, T., Kajitani, T., Kameoka, D.,
Redenbach, M., Shinkawa, H., Nimi, O., and Kinashi, H., “Physical Map of the
Linear Chromosome of Streptomyces griseus.” Journal of Bacteriology. 1995.
Volume 177. p. 6492-6498.] [12]

[12. Paananen, A., Mikkola, R., Sareneva, T., Matikainen,
S., Anderson, M., Julkunen, I., Salkinoja-Salonen, M., and Timonen, T.
“Inhibition of Human NK Cell Function by Valinomycin, a Toxin from Streptomyces
griseus in Indoor Air” Infection and Immunity. 2000. Volume 68. p.
165-169.] [13]

[13. Cohen, A., Bar-Nir, D., Goedeke, M., and Parag, Y. “The
integrated and free states of Streptomyces griseus plasmid pSG1” Plasmid. 1985.
Volume 13. p.41-50.] [14]

[14.Nishida, H., Ohnishi, Y., Beppu, T., and Horinouchi S.
“Evolution of γ-butyrolactone synthases and receptors in Streptomyces”
Environmental Microbiology. 2007. Volume 9. p. 1986-1994] [15]

[15. Sidhu, S., Kalmar, G., Willis, L., and Borgford, T.
“Streptomyces griseus protease C. A novel enzyme of the chymotrypsin
superfamily.” Journal of Biological Chemistry. 1994. Volume 269. p.
20167-20171] [16]

[16. Mellor, J.A., Kingdom, J., Cafferkey, M., Keane, C.T.
“Vancomycin toxicity: a prospective study.” Journal of Antimicrobial
Chemotherapy. 1985. Volume 15. P.773-780. ] [17]