Влияние индуцирующих и селективных агентов на биосинтез нового антистафилококкового антибиотика батумина
Использование высоких концентраций антистафилококкового антибиотика батумина для повышения биосинтетической активности собственного штамма-продуцента позволило отобрать варианты с повышенной продуктивностью. Максимально активный клон Pseudomonas batumici № 9 синтезировал 60—70 мг/л батумина, что в...
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Чуркина, Л.Н. Кравец, А.Н. Клочко, В.В. 2019-06-19T12:25:08Z 2019-06-19T12:25:08Z 2007 Влияние индуцирующих и селективных агентов на биосинтез нового антистафилококкового антибиотика батумина / Л.Н. Чуркина, А.Н. Кравец, В.В. Клочко // Біополімери і клітина. — 2007. — Т. 23, № 2. — С. 108-114. — Бібліогр.: 24 назв. — рос., англ. 0233-7657 http://dx.doi.org/10.7124/bc.00075C https://nasplib.isofts.kiev.ua/handle/123456789/156995 615.33.015.4:579.861.2.07 Использование высоких концентраций антистафилококкового антибиотика батумина для повышения биосинтетической активности собственного штамма-продуцента позволило отобрать варианты с повышенной продуктивностью. Максимально активный клон Pseudomonas batumici № 9 синтезировал 60—70 мг/л батумина, что в 2 раза превышало активность наиболее продуктивного природного штамма. Однако при хранении этой культуры в неселективных условиях наблюдалась постепенная потеря активности. Хлортетрациклин, использованный для увеличения выхода батумина, обладал селективным действием, в результате чего возрастало содержание клонов с повышенной активностью Використання високих концентрацій антистафілококового антибіотика батуміну для підвищення біосинтетичної активності власного штаму-продуцента дозволило відібрати варіанти з підвищеною продуктивністю. Максимально активний клон Pseudomonas batumici № 9 синтезував 60—70 мг/л батуміну, що в 2 рази перевищувало активність найпродук тивнішого природного иітаму. Однак при зберіганні цієї культури в неселективних умовах спостерігалася поступова втра та активності. Хлортетрациклину, який використовували для збільшення виходу батуміну, притаманна селективна дія, в результаті чого зростав вміст клонів з підвищеною активністю. pplication of high concentrations of antistaphylococcal antibiotic batumin in order to increase biosynthetic activity of the own strain-producent allowed selecting variants with increased pro ductivity. Clone Pseudomonas batumici No. 9 with maximum activity synthesized from 60 to 70 mg of batumin per I of culture medium, which was 2 times higher than the activity of the most productive natural strain-producent However, after storage of this culture in non-selective conditions we noticed gradual decrease in the activity. Chlortetracy dine possesses only selective influence, the result of which was raise in the content of clones with the increased activity in producent's population. ru Інститут молекулярної біології і генетики НАН України Біополімери і клітина Біомедицина Влияние индуцирующих и селективных агентов на биосинтез нового антистафилококкового антибиотика батумина Вплив індукуючих і селективних агентів на біосинтез нового антистафілококового антибіотика батуміну Impact of inductive and selective agents on biosynthesis of new antistaphylococcal antibiotic batumin Article published earlier |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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DSpace DC |
| title |
Влияние индуцирующих и селективных агентов на биосинтез нового антистафилококкового антибиотика батумина |
| spellingShingle |
Влияние индуцирующих и селективных агентов на биосинтез нового антистафилококкового антибиотика батумина Чуркина, Л.Н. Кравец, А.Н. Клочко, В.В. Біомедицина |
| title_short |
Влияние индуцирующих и селективных агентов на биосинтез нового антистафилококкового антибиотика батумина |
| title_full |
Влияние индуцирующих и селективных агентов на биосинтез нового антистафилококкового антибиотика батумина |
| title_fullStr |
Влияние индуцирующих и селективных агентов на биосинтез нового антистафилококкового антибиотика батумина |
| title_full_unstemmed |
Влияние индуцирующих и селективных агентов на биосинтез нового антистафилококкового антибиотика батумина |
| title_sort |
влияние индуцирующих и селективных агентов на биосинтез нового антистафилококкового антибиотика батумина |
| author |
Чуркина, Л.Н. Кравец, А.Н. Клочко, В.В. |
| author_facet |
Чуркина, Л.Н. Кравец, А.Н. Клочко, В.В. |
| topic |
Біомедицина |
| topic_facet |
Біомедицина |
| publishDate |
2007 |
| language |
Russian |
| container_title |
Біополімери і клітина |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| format |
Article |
| title_alt |
Вплив індукуючих і селективних агентів на біосинтез нового антистафілококового антибіотика батуміну Impact of inductive and selective agents on biosynthesis of new antistaphylococcal antibiotic batumin |
| description |
Использование высоких концентраций антистафилококкового антибиотика батумина для повышения биосинтетической активности собственного штамма-продуцента позволило отобрать варианты с повышенной продуктивностью. Максимально активный клон Pseudomonas batumici № 9 синтезировал 60—70 мг/л батумина, что в 2 раза превышало активность наиболее продуктивного природного штамма. Однако при хранении этой культуры в неселективных условиях наблюдалась постепенная потеря активности. Хлортетрациклин, использованный для увеличения выхода батумина, обладал селективным действием, в результате чего возрастало содержание клонов с повышенной активностью
Використання високих концентрацій антистафілококового антибіотика батуміну для підвищення біосинтетичної активності власного штаму-продуцента дозволило відібрати варіанти з підвищеною продуктивністю. Максимально активний клон Pseudomonas batumici № 9 синтезував 60—70 мг/л батуміну, що в 2 рази перевищувало активність найпродук тивнішого природного иітаму. Однак при зберіганні цієї культури в неселективних умовах спостерігалася поступова втра та активності. Хлортетрациклину, який використовували для збільшення виходу батуміну, притаманна селективна дія, в результаті чого зростав вміст клонів з підвищеною активністю.
pplication of high concentrations of antistaphylococcal antibiotic batumin in order to increase biosynthetic activity of the own strain-producent allowed selecting variants with increased pro ductivity. Clone Pseudomonas batumici No. 9 with maximum activity synthesized from 60 to 70 mg of batumin per I of culture medium, which was 2 times higher than the activity of the most productive natural strain-producent However, after storage of this culture in non-selective conditions we noticed gradual decrease in the activity. Chlortetracy dine possesses only selective influence, the result of which was raise in the content of clones with the increased activity in producent's population.
|
| issn |
0233-7657 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/156995 |
| citation_txt |
Влияние индуцирующих и селективных агентов на биосинтез нового антистафилококкового антибиотика батумина / Л.Н. Чуркина, А.Н. Кравец, В.В. Клочко // Біополімери і клітина. — 2007. — Т. 23, № 2. — С. 108-114. — Бібліогр.: 24 назв. — рос., англ. |
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| fulltext |
Impact of inductive and selective agents on biosynthesis
of the new anti-staphylococcal antibiotic batumin
L. N. Churkina, A. N. Kravets, V. V. Klochko
Institute of microbiology and virology, NAS of Ukraine
154, Acad. Zabolotny Str., Kyiv, 03143, Ukraine
churkina@imv.kiev.ua
Application of high concentrations of antistaphylococcal antibiotic batumin in order to increase biosynthetic
activity of the own antibiotic producing strain allowed selecting variants with increased productivity. Clone
Pseudomonas batumic No.9 with maximum activity synthesized from 60 to 70 mg of batumin per l of culture
medium, which was 2 times higher than the activity of the most productive natural producing strain However, after
storage of this culture in non-selective conditions we noticed gradual decrease in the activity. Chlortetracyclin
possesses only selective influence, the result of which was raise in the content of clones with the increased activity
in producing strain population.
Key words: batumin, chlortetracycline, antibiotic producing strain, S. aureus
Introduction. Antibiotic batumin had been isolated
from the “Pseudomonas batumic” in the Institute of
Microbiology and Virology of National Academy of
Sciences of Ukraine. Chemical structure of batumin
was shown to be (2E, 10Z, 12E)-20-(3-
aminocarboxy-2-methyl-1-oxybutyl)-amino-7-methyl
ene-17-oxo-19-oxy-3,5,15-trimethyl-eicosa-2,10,12-tr
ienoic acid [1]. Due to its unique chemical structure,
batumin can be considered as new antimicrobial
compound with no analogues among commonly used
antibiotics. Batumin has unique and selective activity
against all investigated types of staphylococci [2, 3],
and is considered to be a highly effective therapeutic
agent for the treatment of nasal staphylococcus carriage
[4, 5].
The diagnostic preparation "Diastaph"
(batumin impregnated disks) ensures quick and reliable
identification of microorganisms of genus
Staphylococcus [6]. The disks may be successfully used
when providing regular hospital examination on nasal
carriage of staphylococci. There are enough evidences
to consider batumin as a promising therapeutic agent
against hospital staphylococcal infections – one of the
most urgent and yet not solved problems of modern
medicine. Some disadvantages of natural antibiotic
producing strain, is a low level of antibiotic
biosynthesis (20–25 mg/l), which creates serious
obstacles on the way to its industrial production.
The use of antibiotics as selective and inducing
agents allowed obtaining some practically important
results. Thus, highly active mutants of ristomycin,
chlortetracycline, and imbricin producing strains were
selected under the influence of antibiotics on producing
cultures of actinomyces [9–12].
The goal of current work was to investigate the
specificities of batumin and chlortetracycline effects on
108
ISSN 0233-7657. Biopolymers and cell. 2007. Vol. 23. ISS 2. Translated from Ukrainia
BIOMEDICINE
ã L. N. CHURKINA, A. N. KRAVETS, V. V. KLOCHKO, 2007
biosynthetic activity of antibiotic producing strain with
the purpose of increasing of its productivity.
Materials and Methods. The strain "P. batumici"
109 with increased biosynthetic activity has been used
throughout the study [7]. It is a derivative of wild strain
"P. batumici" B-303, selected among the clones during
passages of the parental strain. Batumin and
tetracycline resistant variants of "P. batumici" 109 were
obtained using the method of step-wise selection with
increasing antibiotics concentration. The
agar-containing media was supplemented with batumin
and chlortetracycline dissolved in water. Minimal
inhibiting concentration (MIC) of batumin and
chlortetracycline for "P. batumici" 109 were 200 ìg/ml
and 0.2 ìg/ml, respectively.
"P. batumici" 109 and batumin-resistant variants
No.4 and No.9 and chlortetracycline-resistant variants
No, 28, 53, and 80 were kept in non-selective
conditions layered with mineral oil on 0.5% of MPA.
To study the changes in antibiotic production, all "P.
batumici" variants were inoculated at the density of
1C107 cells per ml into 150 ml of synthetic growth
media The cultivation was performed using a shaker
(220 rpm) in Erlenmeyer flasks (750 ml) at the
following conditions: 150 ml of nutrition medium,
initial concentration of cells was 1C107 cells per ml, T =
25°C, cultivation time – 72 hours.
Biosynthetic activity of "P. batumici" clones was
assessed using the worked-out method on MPA with
the replicator, calculating for 5 clones per cup, using
batumin-highly sensitive test-culture of
Staphylococcus aureus 209 P (UKM B-918, ATCC
6538P), i.e. using the method of batumin diffusion into
agar.
Based on the diameter of zone of growth inhibition
of test Staphylococcus aureus 209 P, clones were
sub-divided as low-active – with 5–20 mm zone of
inhibition, active – 20–30 mm, with increased activity –
30–40 mm, and highly active – 40–60 mm.
Quantitative concentrations of antibiotic in cultural
medium were determined by spectrophotometry.
Cultural medium was extracted by chloroform.
Obtained extract was steamed in vacuum-steamer at
40–45°C with the following purification using the
method of thin-layer chromatography. Batumin
containing sorbent was removed from chromatographic
plate and eluted with alcohol. Batumin concentration in
the solution obtained was determined using the method
of spectrophotometry and calculated according to the
following formula [8]:
C
D P
E
=
* *
%
104
1
where: C – batumin concentration, mg/l; D – optical
density of the batumin solution at l = 225 nm; P – total
dilution of the sample; E1% – extinction coefficient of
1% batumin solution (E1% = 584); 104 – concentration
recalculation coefficient per 1 l of cultural medium.
Results and Discussion. The possibility of
increasing batumin synthesis using the target product in
selection was studied at the first stage of our work.
Using the method of stepwise selection, the variants of
“P. batumici” 109 resistant to different batumin
concentrations (400, 800, 1200, and 2000 mkg/ml)
were obtained, which was necessary in order to analyse
the dependence of their productivity on the level of
resistance to own antibiotic. According to hypothesis
there was a direct correlation between the productive
cell and the ability to grow on higher antibiotic
concentrations, thus, the most productive cells would
grow on the highest concentrations.
It was found that the rate of bacterial survival
decreased along the concentration increase from 200 to
up to 2000 mkg/ml. Single clones with the level
survival of 0.05% were formed at the concentration of
2000 mkg/ml. Batumin-resistant colonies were
different from corresponding batumin-sensitive
colonies by a number of morphological characteristics,
namely, they were rough, of smaller size, and some of
them were mucous. Next, 1359 clones were selected for
further experiments.
The analysis of "P. batumici" 109 clones for
synthesis of antibiotics revealed uneven level of
antibiotic biosynthesis by some cells. The populations
were dominatd by active clones (46.7±3.1%) and the
clones with increased activity (52.1±3.4%).
Batumin-resistant variants demonstrated dependency
between the level of specific activity and the level of
antibiotic resistance. The increase in batumin resistance
level was followed by the increased number of clones
with increased activity and highly active clones as well
(Fig.1). It is noteworthy that within the concentration
109
IMPACT OF INDUCTIVE AND SELECTIVE AGENTS ON BIOSYNTHESIS
range from 1200 to 2000 mkg/ml, active variants had
been replaced by highly active clones.
It has been assumed that the variants with the
highest batumin-resistance have to be of increased
biosynthetic activity. The search for maximally active
variants was performed among 453 highly active
clones, obtained in five independent experiments and
different in the level of resistance to antibiotic. The
largest growth inhibition zones of S. aureus 209P (47
and 58 mm) had been given by two clones, No.4 and
No.9, with the level of resistance 2000 mkg/ml (Fig.2).
These clones were synthesised at the level of 52–58 and
65–70 mg/l of antibiotic, respectively. Therefore,
comparing to the parental strain of "P. batumici"
(batumin output 31.4±1.9 mg/l), the selected variants
of"P. batumici" No.4 and No.9 had average 2–2.5 times
increase in the yield of antibiotic.
As the stability of level of antibiotic synthesis is of
great practical importance, we have investigated the
stability of variant No.9 after storing for 20 and 60
days. When the stocks were plated to obtained
independent clones, it was found that the significant
variations of specific activities in their populations. of
batumin-resistant highly-active clone No.9 to single
clones revealed their significant activity-wise
distribution.
Thus, after 20 days the clones with increased
activity (71±2.5%) and highly-active ones (29±1.4%)
dominated, while after 60 days this ratio had been
changed, and the clones with increased activity
(53.7±2.1) and active clones ( 43.5±1.9%) began to
prevail in population dominant with diminishing of
highly-active clones to 2.8±0.004% (Fig.3).
These ratios were observed on storing of the
clones on batumin-free medium, i.e. gradual decrease
in activity was observed in the course of storing. The
culture achieved its initial state and synthesised 35-40
mg/l of batumin. Similar situation was observed when
investigating the stability of variant No.4.
The experiments performed show that batumin
may be used for increasing the biosynthetic activity of
antibiotic producing strain of its own. However, it is
worth mentioning that obtained highly-active clones
are characterized by relative stability and, therefore,
can be used for obtaining of antibiotic at the laboratory
conditions only.
Taking into account the information on successful
application of other types of antibiotics in order to
increase the level of target product output, we decided
to study the influence of chlortetracycline on batumin
synthesis. Tetracyclines belong to the class of
antibiotics which inhibit protein synthesis by means of
modification of proteins of translational apparatus of
target cell [13, 14], and batumin belongs to
membrane-acting antibiotics [15, 16], therefore, the
manner of action of these antibiotics on antibiotic
producing strain cells will be different.
“P. batumici” 109 variants, resistant to different
concentrations of chlortetracycline (2, 20, 40 mkg/ml)
were obtained using the method of step-wise selection.
Preliminary experiments were dedicated to the study of
survivability of "P. batumici" 109 cells depending on
the level of resistance. As it has been supposed,
increase in resistance of chlortetracycline resulted in
significant decrease in survivability of producing strain
110
CHURKINA L. N., KRAVETS A. N., KLOCHKO V. V.
Fig.1 Variability of activity degree of “P. batumici” 109
clones, induced with batumin: 1 – low active; 2 – active; 3 –
increased activity; 4 – highly-active (a – before selection, b –
after selection)
111
IMPACT OF INDUCTIVE AND SELECTIVE AGENTS ON BIOSYNTHESIS
Fig.2 The growth inhibition zones of test-culture S. aureus 209P: a – “P. batumici” 109; b, c – batumin resistant variants of
clones No.4 and No.9 with increased level of antibiotic biosynthesis
Fig.3 Distribution of clones
according to their activity of
batumin-resistant variant of "P.
batumici" No.9 at storing: 1 –
low active; 2 – active; 3 –
increased activity; 4 –
highly-active
cells. At the concentration of antibiotics of 2 ìkg/ml,
the number of survived bacteria amounted to 8%, and at
the concentration of 20 and 40 mkg/ml, 0.8% and
0.05% of bacteria survived, respectively.
The results of investigation of correlation of
antibiotic producing strain clones according to the
degree of their activity at the interaction with
chlortetracycline showed significant increase in
population of clones with increased activity and
decrease in number of active clones. Meanwhile, in the
population of "P. batumici", highly-active clones were
not detected (Table).
Further research was to study the influence of
maximally active clones according to batumin
synthesis among the clones with increased activity and
the level of survivability of 0.8 and 0.05%. 760 clones
of resistant to chlortetracycline variants (20 and 40
ìkg/ml) were selected for further research. Differential
analysis of clones according to batumin synthesis
allowed detecting three clones – No.28, 53 and 80 with
diameter of zone of growth inhibition S. aureus 209 P,
39, 35, and 37 mm, respectively, in comparison with 30
mm of "P. batumici" 109. The productivity of these
clones was 35–40 mg/l of batumin, which did not
exceed significantly biosynthetic activity of "P.
batumici" 109.
Although among chlortetracycline-resistant
variants of "P. batumici" 109 we did not reveal the
clones with increased biosynthetic activity, antibiotic
possessed certain selective activity, which consisted in
purifying natural population from low active and active
clones.
Antibiotics are often referred to as cytotoxic
metabolites for bacteria that produce them. The
resistance of many antibiotic producing strain towards
them is determined by energy-dependent efflux
systems, which carry toxic products out of the cell
[17–20]. It is worth mentioning that the increase in
activity of such systems may cause the increase in
antibiotic output. In particular, it has been
demonstrated for 6-dimethylchlortetracycline [21],
surfactin and pliplastin [22], fenarimol and penicillin
[23], cephalosporin C [24].
To our mind, the increase in antibiotic output at
selective passages of culture on the media with
increased batumin concentrations is determined by its
more active removal out of the cell, which is the main
mechanism of producing strain detoxication for its
toxic product. It is also possible that the synthesis of
antibiotic increases in accordance to the feedback
mechanism, but the solution to this problem is far
beyond the framework of this work.
Positive chlortetracycline effect may be due to the
selection of cells with highly-active efflux pumps. It is
possible that "P. batumici" uses a special pump for
batumin removal, which is in good correlation with
different effects of batumin and chlortetracycline
presence in growth medium.
Therefore, having investigated the effect of
batumin and chlortetracycline on biosynthetic activity
of antibiotic producing strain, it has been shown that
batumin initiates the appearance of highly-active
clones with increased productivity in "P. batumici" 109
population, while chlortetracycline is specific for its
112
CHURKINA L. N., KRAVETS A. N., KLOCHKO V. V.
Table The percentage distribution of specific activity among individual clones in population of "P. batumici" 109 after
chlortetracycline effect
Chlortetracycline
concentration,
ìg/ml
The number of
clones reviewed
Content of clones in population, %
Low active Active Increased activity
Control 105 1.2±0.06 46.7±2.8 52.1±3.1
2 122 0 47.5±2.9 52.5±3.0
20 125 0 24.7±1.5 75.3±4.1
40 118 0 10.8±0.9 89.2±5.0
selective activity only, as a result of which the number
of clones with increased activity increases.
Conclusions. For the first time, the possibility of
increasing the synthesis, using the selection of the
target product, has been shown for producing strain of
anti-staphylococcal antibiotic batumin.
The use of batumin in selection of antibiotic
producing strain allowed obtaining a relatively stable
producing strain with batumin output more than 2-fold
increased.
During selection of antibiotic producing strain with
chlortetracycline, highly-active clones have not been
detected, however, the effect of this antibiotic in
population of producing strain population revealed the
decrease in the number of low active and active clones
and the increase in the number of clones with increased
activity. Chlortetracycline was shown to be of selective
activity, purifying natural population from low active
and active clones.
Ë. Í. ×óð êè íà, À. Í. Êðà âåö, Â. Â. Êëî÷ êî
Âëè ÿ íèå èí äó öè ðó þ ùèõ è ñå ëåê òèâ íûõ àãåí òîâ íà áè î ñèí òåç íî âî ãî
àí òèñ òà ôè ëî êîê êî âî ãî àí òè áè î òè êà áà òó ìè íà
Ðå çþ ìå
Èñïîëü çî âà íèå âû ñî êèõ êîí öåí òðà öèé àí òèñ òà ôè ëî êîê êî âî ãî àí òè -
áè î òè êà áà òó ìè íà äëÿ ïî âû øå íèÿ áè î ñèí òå òè ÷åñ êîé àê òèâ íîñ òè ñî -
áñòâåí íî ãî øòàì ìà-ïðî äó öåí òà ïî çâî ëè ëî îòî áðàòü âà ðè àí òû ñ
ïî âû øåí íîé ïðî äóê òèâ íîñ òüþ. Ìàê ñè ìàëü íî àê òèâ íûé êëîí
Pseudomonas batumici ¹9 ñèí òå çè ðî âàë 60—70 ìã/ë áà òó ìè íà, ÷òî â 2
ðàçà ïðå âû øà ëî àê òèâ íîñòü íà è áî ëåå ïðî äóê òèâ íî ãî ïðè ðîä íî ãî
øòàì ìà. Îäíà êî ïðè õðà íå íèè ýòîé êóëü òó ðû â íå ñå ëåê òèâ íûõ óñëî -
âè ÿõ íà áëþ äà ëàñü ïî ñòå ïåí íàÿ ïî òå ðÿ àê òèâ íîñ òè. Õëîð òåò ðà öèê -
ëèí, èñ ïîëü çî âàí íûé äëÿ óâå ëè ÷å íèÿ âû õî äà áà òó ìè íà, îá ëà äàë
ñå ëåê òèâ íûì äå éñòâè åì, â ðå çóëü òà òå ÷åãî âîç ðàñ òà ëî ñî äåð æà íèå
êëî íîâ ñ ïî âû øåí íîé àê òèâ íîñ òüþ.
Êëþ ÷å âûå ñëî âà: áà òó ìèí, õëîð òåò ðà öèê ëèí, øòàìì-ïðî äó öåíò,
Staphylococcus aureus.
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ÓÄÊ 615.33.015.4:579.861.2.07
Íàäiéøëà äî ðå äàêöi¿ 02.11.06
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CHURKINA L. N., KRAVETS A. N., KLOCHKO V. V.
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