Note: Descriptions are shown in the official language in which they were submitted.
~576~ -
: .
.,`:
GERMICIDAL AGENT .~ ~
Disinfectants and antiseptics comprlsing quaternary ~ :
ammonium or sulfonuim salts are known and find wide
application. :
The compounds known as "quats" wh.ich are added include -:~
a large variety of compound types, in which -the common
characteristic is a quaternary ni-trogen or sulfur a-tom.
The best known is alkyldimethyl benzyl ammonium chloride.
Other than this there is also a series bactericidal quats, .
which belong to the groups of alkyl pyridinium salts
or cetyl trimethyl ammonium salts. Alkyl imidazoleum
salts and benzo triazoleum salts also possess a good
bacteriostatic activity. ~ :
Other quats, which are derived ~rom isoquinoline, such as - : .
lauryl isoquinoline, in addition to bactericidal activity,
also possess a good fungistatic activity.
It is also known that in the presence of non-ionic
tensides, the bactericidal and fungicidal activity of
quats is signlficantly reduced.
.. ~...
I o
,
':
.. , ,,. , -. . , . - . . ., . , ... . .. . . , .. . . -:,
57~4
:
Furthermore, it is known that phosphonium saltS, phenols r
phenol esters, amphotensides, aldehydes, polyvinylpyrrolidone- ;
I - complexes, amine oxides and/or amine imides possess a
germicidal activity.
The invention concerns the surprising finding that the
biological activity of the abovem~ntioned known germicidal
agents can be synergistically increased by the addition
of compounds described in more detail below. :. :
,,. ~; . ~ :
Thus, in accordance with the present teachings, a germicidal .... ~
:;,
agent is provided which has a germicidally active quaternary ~ -
j ammonium salt, sulfonium salt, phosphonium salt, phenol,
phenol ester, amphotenside, aldehyde, polyvinyl pyrrolidone~
I2-complex, amine oxide, or amine imide, to which has been
added a compound of the general formula~
Rl - S R2
()n
~` in which n is 0, 1 or 2, ~ :
:I Rl is an alkyl of 6 to 18 carbon atoms, and - .~ `
j R2 lS an alkyl of 1 to 18 carbon atoms, aralkyl, ;
,' 20 hydroxyalkyl having 2 to 4 carbon atoms, -(-CE12-
CH2-O-)m or -(-CH-CH2-O)m in which m is a whole
3 .:~:: ?
~ number of from 1 to 12, and R3 is CH3, -CH2Cl :: :
.~ .
1 or C2E~5
.i ':,' :.
~1 .;'. .. .
:i! ~, . ~ .
i 30
. ' :
1 ~2-
.-, ~ ' ,``' :
The compounds of formula I addecl in accordance with the
invention can be produced in known manner. The compounds
are neutral substances which in general possess the
properties of non-ionic tensides. They posses a low
biological activity so that it can be regarded as most
surprising that a mixture of the said germicidally active
1 , :
compounds with substances of the general formula I .
exhibit a synergistic increase in activi~y. One would
much rather expect a decrease in biological activlty ;
i on the basis of the known lowering of bactericidal
1, and fungicidal activity by non-ionic ~ensides.
~'.fl .
The quats which come into question in accordance with
the invention are similarly produced by known processes.
~, The germicidal agents in accordance with the invention ` .
3~ ~ particularly possess a significantly increased activity .
.1 against skin pathogenic fungi as against the known
compounds, which is of particular importance in the
I cllnical area.
1 .
;I The phosphonium salts which come into question in. ~. .
. , .
. accordance with the invention correspond to the formula:
PRlR2R3R~ ~) X ~3 ~
:" 1 .:
.-,. ::
.~ i . , . . -
.: I .
`'- 3
:~ - 3 _ ~ ~
. ... ,, .. . , . : .,
~2~576S4
` .
in which preferably one of the radica]s Rl to R~ is
straight-chained alkyl of 10 to 16,particularly 12 to
14, carbon atoms, whilst the other radicals are alkyl ~-
o~ 1 to 4 carbon atoms, whereby one o these can also
be benzyl, particularly methyl, and X ~ is the usual
anion for this known germicidally active phosphonium
salt, perferably chlorine- Particularly, the phosphonium
salts consist of dodecyltrimethyl-phosphoniumchloride
or dodecylc~imethylbenzylphosphoniumchloride.
The germicidally active phenols which may be employed
in the germ;cidal agent o the invention are preferably
chloro phenols, particularly mono-chlcro phenols, di-
chloro phenols, tri-chloro phenols or penta-chloro
phenol, or phenols having a lower alkyl of 1 to 4 carbon
atom substituent, particularly cresols.
~1) ' ' , ' .'
~! The germicldal phenol ester which is preferably employed
in accordance with the invention, consist of phenols,
such as defined above, in particular pentachloro phenol,
! and ~ranched or straight-chained fatty acids with up to :~
18 carbon atoms, preferably up to 6 carbon atoms, especially
3 butyric acid.
; :~
:; I ,'. ~:
1 - 4 ~
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., . . ~ . . . 1
'.'. ' ' `' ' ''
54
,~
The amphoten$ides, in which the known germicidal activity ~.
can be synergistically increased by the addition of
compounds of formula I, are tensides with several
functional groups which can ionise in aqueous solution : .
and thus, dependent on the nature of the medium, lend .
to the compound an anionic or cationic character.
The amphotensides preferably consist of compounds of
the following formula:
.''', ~
~, ' . `, ~
: ,2
R1 ~ co~r ~ (CE~2)X - N2~ (CH2)y COO ;~
:l ~2 - :
,1 , .
l R1 - CO~ ~ (CH2)x- N0~ ~CH2)~ S03
:........................................ 3
, . . ',
R1 ~ N _ (CH2)~ S3 .
~ 3
.-", . : :
R2 '' ''
l, R1 ~ N~ - (CH2~y COO
:~ . 3
~ . . . .
~` . R4 - NH - ~CH2)xcooMe .~ ~
j R~ - NH(CH2)xNH(CH2jxCOOMe or ~ ; :
Rl-NH-~cH2)~-NH-(cH2)x-NH-cH2-cooH
;'~ . ' ~.:
'. , `
~L~5~6~4
in which Rl is a long chain saturated or unsaturated
alkyl ~roup preferably having lO to 14 carbon atoms,
R2 and R3 are lower alkyl having 1 to 4 carbon atoms, : ~:
particularly methyl or e~hyl, x is a whole number from
1 to 3, y is a whole number from 2 to 3, Y is -NH-or-O-,
R4 is a saturated or unsaturated alkyl group having
:j ~
. 8 to 18 carbon atoms, particularly an oleic group, and
Me is an alkali metal, particularly Na. ;~
; :~
The germicidal aldehydes which are preferably employed
in the germicidal agent of the in~ention, consist of ~.
saturated aliphatic mono- and di-aldehydes havin~ up to ~
i lO carbon atoms, in particular formaldehyde, acetaldehyde, ~.
.:l glyoxal glutaraldehyde, succinic dialdehyde, 2-ethyl ~
I hexanal, or substances which release aldehydes, in ~ :
. :i, .
~, particular in acetylated form. .;.;.~
~. : : -: .
., The amino oxides correspond to the formula : :
~::3
R - N ~
! R2
. ~ . ' `, ':
wherein R ls preferably a straight or branched long ~ :
chain alkyl radical with 10 to 18, particularly 12 to 14,
., ... ,~; , .
'1 , :~ ,
'.: 1 ~ , ' ','
- - 6 - - :
;,, ' . , : ., . ~
5 715~4
carbon atoms and Rl and R2 is lower alkyl or oxalkyl
with 1 to 4 carbon atoms, particularly methyl or
2-hydroxy ethyl.
. ; .
The amine imides which may be employed may be of the
formula~
` . 1 '
~ R - CO ~ ~ N ~ - R2
,, \ .
.
.
wherein, preferably, R is a straight or branched long
chain alkyl radical having 10 to 18, particularly
'~ 12 to 14, carbon atoms and Rl, R2 and R3 are lower
alkyl or oxalkyl radicals with 1 to 4 carbon atoms,
particularly methyl or methoxy radicals.
:-~
:~
The polyvinylpyrrolidone - I2 ~ complexes which ~
~1 may be incorporated in accordànce with the invention -
.,~
! are similarly known as germicides.
~ , ~ ... .. .
;~ Preferably, the compounds of formula I which are added
. : ::
in accordance with the invention are those in which Rl ~
: , ~., ,- .
~ is an alkyl radical having 8 to 14 carbon atoms. R~ is
~ .
.. ,
.; . , ~ .
~~ - 7 ~`
. ' . .
l~S ~s554
.,
preferably an alkyl radical having 1 to 7 carbon atoms
and in the case of an aralkyl radical is preferably a
phenyl alkyl or benzyl radical. Preferably n signifies a
whole number from 1 to 6.
, . . . .
:, :
In the germicidal agents in accordance with the invention,
any desired ratio of the quaternary ammonium salts,
. .
sulfonium salts, phosphonium salts, phenols, phenol
esters, amphotensides, aldehydes, polyvinylpyrrolidone~
.`'! I~ - complexes, amine oxides and/or amine imides to
.`! ;:;
the compounds of the general formula I can be maintained.
Preferably however the weight ratio of the said compounds
to the compounds of the genera~ formula I varies between
95:5 and 5:95, and most preferably stoichiometric ratios
are maintained. With regard to the disinfectant activity,
the cross-linking activity,as well as the detergent
activity, the respective ratios can be determined. This
~ .
i determination may be made by simple preliminary experments.
The germicidal agents in accordanoe with the invention may,
dependent on its use, be employed as such or in mixture
with an inert carrier or diluent and/or in combination
, ::' :,:.
i with other structuring, washing, cleaning and water
:', '; ' ~ .':`.'
~ ~ ~ softening agents.
~.-1 : . . , ~., .
~ ~ - 8 -
; ~ . ' . . ;~
.. :; -, . . .
5~54
Examples of inert carriers or diluents are the ~ollowing:
' , ;:.:
propellants, such as carbon dioxide, fluorine
carbohydrates, fluortne-chlorine carkohydrates, ethanol,
isopropanol, dimethylsulfoxide, water, talcum, silica
gel, carbohydrates, such as lower paraffins, and salts,
such as sodium sulfate.
Preferably, the agents of the invention are employed in
the form of f]uids, solutions, emulsions, suspenslons,
sprays, powders, salts etc.
,.;,.
Examples of additional components of a combined cleaning and
i disinfectant agent are silicates, such as sodium meta-
silicate carbonates, such as sodium carbonate, as well
as polymeric phosphates, such as ~etra-sodium triphosphate.
The germicidal agents of the invention are of particular
importance in the clinical area.
j ..
.. . ..
' With the addltion of compounds of formula I to higher
`i1 chlorinated phenols, such as for example pentachloro
! phenol, which until now it has only been possible to
keep and use in alkaline solution, whilst it precipitates
out in aqueous acid medium, the advantage is obtàined
, :
in a surprising manner~that such chlorinated phenols can
also be added to aqueous acid medi~s~
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., . ` .
~ ~ .
. q . .
: ~ _ 9 _
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.. . .
- . - . ... .. . ... . ~ , ......
1~5~ 4
A further advantage of the germici.dal agents of the
invention consists in that on the one hand the biological
decomposition of the compounds of formula I is practically
complete, whereas in addition the synergistic increase
in activity requires less active agent to be employed,
whereby the pollution effect remains the same or is even
significantly reduced.
Mixtures of quats with compounds of formula I with .
particularly significant synergism are for example '
stoichiometric mixtures of the fol].owing qua.ternary
ammonium and sulfonium salts:
: .
J
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~ 10. r , ,,~
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- ~
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"-', ~ '
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'`'~''.`: ` '' ' . ' . ' '. .' .'. . . .. '''.. . ~ ``' ' ~ ''
s~;s~ : ~
[~12 25 IS CH2~CH2~OH~ CH3-o-so a
CH3
[ n 2n + 1 -N-CE~2 ~ ~ Cle
~ .
[ CH2-CH2O~3 ~ Cle
CH2-cM2oH
¦C12H25-NI C 2 ~~ ] Cl
L 1 3 3 1 -~ -O- (CE~2) 2-- (CH2) 2 ~l -CH2--~ ~ Cl
. CH3 H3C` CH3 :
~',", ~
,'1' [e=~N~)-C16E~33~1,C1;3 `.`~'~
....
'`"1 `~
,'~', ' ' ~
.~ ~ .
~.
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.:, ::
-- 11 --
.,"~
~5'~6~q~
GH3 H3
[cH3-c-cH2-c ~ o-(cEl2)2-o-(cH2)2 N CH2 ~ ] Cl~
CH
[ ~ -0rCH2-cH2-~-cl2H25 ~ Br
LC2 2 ~ Cl~H33 ~ 3r
~CH3)3N-Cl6H33 ¦
. ! ' ,
'' i ' ~ ~
L ~ ] Hr~ ~
. ' ~,','
,: . ,
L , C}12-C}12-CH~ -(CH2)6-N-CH-CH -CH ~ 1 2 Cl~
CH H3 3 H3C CH3 H3C
; . .
.,~ ;
. ~ , ' .
.~,,~ . .
:"~
1 3 0 : :
.'-~ ,
; - 1 2
,; ~ - .
., ~ .
., .
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.. :~ , .. . . . .. . ` . .... : . " - .. , .. . :
11~5765~
with sulfoxides of the formula:
` CnH2n ~ 1 -I-cl~I C 2
O R
wherein n = 8 to 14
and R = -CH3, -C2H5 and CH2Cl :;~
Preferably the following compounds o formula I are added:
CnH2n + 1 ~ S - C~2 CH2 n = 6 - 8
CnH2n ~ S - C~H CH2 n = 8 - 14
O R R = -CH3, -C2H5,
`. 10 -OEI2Cl "
CnH2n + 1 -~S~- CIH CH2 n = 8 - 14
;i O O R R = -CH3cl C2 5,
. j ; .
.' The germicidal activity of the germicidal agents of the
:~ invention is provided by determining the minimum inhibition .
:~ concentration (MIC) in accordance with the procedure
:~ described for example in "Richtlinien zur Prufung chemischer
Desinfektionsmittel - Gustav Fischer Verlag, Stuttgart
~'~ ;. .. .
~3 ~L959)" or in accordance with the inhibition test with -:
2 : graded growth of microorganisms.
20-
` ~ ' ' ;'
: ~ .
'1~ : . ;': ''
;.3 : ~
~l 30
: ~-.`. ! ~ 13 -
: ',', :
The following Examples illustrate the invention, without
; limiting the invention.
::
The Examples 1 to 6 illustrate the addition of quaternary
ammonium and sulfonium salts.
~.', ,; ;~
For carrying out the Exarnples 1 to 4, the agents in`
accordance with the invention are employed in pure form, ;
i.e. without carriers or diluents. The procedure employed
!, follows precisely the aforesaid method of testing chemical
disinfectant agents. The concentrations, which the agents
of the invention are in general employed, correspond to those
~ of the quaternary ammonium compound, i.e. they are employed
i in an amount of from 100 to 200 p.p.m., calculated on the
100% substance. `~
12H25 N - C~12 ~ C1
I ` 3 `
1 ` `` - , ~ : `
' B = Mixture of
28 parts CnH2n ~ ~ CH2 C~2
' and o
¦ 35 parts of compound A ~;
'' ' 1 . :, :'1 ~ ' `. :
"~
... , .
.,, ~ . . . ~ :
".':-~, - ;
7~i5~
Test organism Growth inhibition:
Minimum inhibition concentxation
tMIC) in ~ by weight of agent
A B :~
. Proteus vulgaris 0,00025 0,0005
: Escherichia coli 0,0025 0,0050
Pseudomonas Fluorescens 0,0100 0,0250
Pseudomonas aeruginos 0,0125 0,0250
Staphylococcus aureus 0,0005 0,00025 ~.,
Bacillus subtilis 0,0005 0,00025
Aspexgillus niger 0,005 0,0025
Trichoderma sp. 0,0006 0,0005
Saccharomyces vini 0,001 0,001
Candida albicans 0,0025 0,0025 :
Trichophyton mentagrophytes 0,001 0,0005
Trichophyton rubrum 0,0025 0,0005
; Microsporum gypseum 0,0005 0,00025
Microsporum canis 0,00025 0,0001 :~ :
: Oidium sp. 0,001 0,00025 .
Epidermophyton :~.l.occosum 0,001 0,00025
Saccaromyces cerevisiae 0,001 0,0005
:~ Example 2 3 ;~ ~ .
12 25 f 2
B = Mixture of ;
25 parts C12H25 - ~S CH2 2
:'' . ' ~
and .
35 parts of compound A ~:
., I , ~
~.~ 30 ~ ~
:'' ". .,~
:`, - 15 - :
:: :
7fi~4
Test organism Growth inhibition:
Minimum inhibi.tion concentration
(MIC) in ~ by weight of agent
A B
Escherichia coli 0,0125 0,0125 ~ .
Staphylococcus aureus 0,0010 0,0010
Proteus vulgaris 0,00125. 0,00125
Microsporum canis 0,001 0,00050 ~. :
Aspergillus niger 0,0025 0,00125 :
Saccharomyces cerevisiae 0,0010 0,0005 ~ ::
.pidermophyton floccosum 0,0010 0,00050 ~:
A - Cn~2n + 1 1 CH2 ~ ] n = 12 - 14
B = Mixture of -
P n 2n ~ 1 S - CH2 - CH2 - OH n = 10 - 14
O
;~
n 2n + 1 / \ CH2 ~ CH2 - OH n = 10 - 14
O O "
and 35 parts of compound A
~ Test organism Growth inhibition:
:.' Minimum inhibition conce~tration
' (MIC) in % by weight of agent ; ~`
A B :
Staphylococcus aureus 0,0005 0,00025
Escherichia COlI ` O, 0025 0,0050
, Aspergillus niger 0,005 0,0025
'J ~richodérma `sp. 0,0005 0,00025
"; Trichophyton mentagrophytes 0,001 0,0005 `.
.~ Trichophyton rubrum 0,0025 0,00125
Oidium sp. 0,001 0,0005 ~-
~`', Epidermophyton floccosum 0,001 0,00025
.~ ~
:1~ 30 :
~'.
. - 16 -
:
`~'
,
S7~j5~
Example 4
CH
A C12H25 1 2 ~ Cl~
CH3
B = Mixture of . . ~:
20 parts CnH2n ~ S CH2 2 n = ll - 14 :
O
8 parts C6Hl3 - S CH2 C 2
and 35 parts of compound A
Test organism Growth inhibition ~
Minimum inhibition eoncentration ~ :
(MIC) in ~ weight of a~ent
A B -
Staphylococcus aureus 0,0005 0,00025 :
Baeillus subtilis 0,0005 0,00025
Aspergillus niger 0,005 0,0025
Trichoderma mentagrophytes 0,001 0,0005 :-
Trichophyton rubrum 0.0025 0,0005 ~ :
Microsporum gypseum 0,OOOS 0,0001
Microsporum canis 0,00025 0,0001 `
Saccharomyees eerevisiae 0,001 0,0005
.:
.; ~ ~ . :
- 17
,
- - ~
1`~57~jS~
~: `
The surpris~ng synergistic activlt~ of the germicidal ~ :
agents of the invention are shown by these examples.
,'-~ "'' ',''
The following Examples S and 6 illustrate the addition
of the combination of cleanin~ and disinfectant agents
in accordance with the invention. ::
Example.5 :;
Powder from cleaning and disinfectant agent for the
oodstuff industry
Active agent mixture according to Example 1 B S parts ` ~ :
Anti foaming agent 2 parts
Stearyl alcohol-Polyglycol ether 1 part
Tripolyphosphate 36 parts ;
Sodium carbonate 40 parts
Sodium meta-silicate (nonahydrate~ 16 parts
Example 6
~:,
Liquid disinfectant agent for the foodstuff industry
Aative ayent mixture of Example 3 B 8 parts :~
NTA (Nitrilo triacetic acid Na salt) 2 parts
Potassium hydroxide 50~ 4 parts
water 86 parts
The following Examples 7 to 13 illustrate the addition of :~
further known germicidally active substances
.: , ' ' , ~ ~ ~:'
~ ~ - 18 ~
- ' ' . ' ~ .
, : ; :
EXa~ple 7
ActiYe agent Amount of active agent in the
nutrient solution in parts of
active agent per million parts
of solution
100 7S 50 25 10 5 1 .
pentachloro phenol O O O 1 2 3 5
mixture of
A) 50 parts pentachloro phenol :~
and
B) 50 parts CnH2n ~ CH2CH2H 2 3 ~ : O '~
n = 11 to 14
.: .
''
Example 8
Active agent ~mount of active agent in the
nutrient solution in parts o - .
active agent per milli.on parts
of solution
100 75 50 2510 5
Mixture of
A)50 parts pentachlorphenol, ` :`
10 parts glutaraldehyde and . ;
B)40 parts CnH2n -~ 1 S CH2CH2H o 3 2
Q ~
n= 11 to 14 .
In the Table .
:,. ... ..
O = no fungus growth . i~
graded to 5 = uninhibited growth - `;~
.. . ~ . .
" ~ '
- 19 ~ ~`":
.: '
~5~
E~ample 9
A = [CI2 H25 - P~ - CH3 ] Cl~ ~
3 :
B = Mixture of 50 parts
CnH2n + 1 ~ I CH2C~2 n = C11-14 AlkYl
O ~:
and .
50 parts of compound A : -
Test Organism Growth inhibition: ~
Minimum inhibition concentration ~ :
(MIC) in ~ by weight of active agent
A B
Aspergillus niger 0,005 0,0025
Candida albicans 0,0025 0,0025 ~ ~.
Microsporum canis 0,00025 0,0001 .
Epidermophyton floccosum 0,001 0,00025
Saccaromyces cerevisiae 0,001 0,0005 ~ .
. : ~
Example 10
H CH
A = C11 H23 CO N - CH2 CH2 CH2 ~ ~ CH2 ;~
.
, :
.;: ,
' ~'" .
.
~ '
: - 20 - .
:~
. . , , ~ ,
~.~35 ~
B = Mixture of 50 parts
Cn H2n + 1 ~ S ~ CH2 CH2 n = 11 to 14
d ~ :
50 parts of cornpound A
~ ~ .
Test organism Growth inhibition: ~ :
Minimum inhibition concentra-,
tion (MIC) in ~ by weight ~ . .
of active agent - :
A B
Trichoderma sp. 0,010 0,005 . .
Staphylococcus aureus 0,001 0,0025
Epidermophyton ~loccosum 0,005 0,001 ~ ~
Example ll .,
A = Polyvinylpyyrolidone I2 ~ Complex
B = Mixture of 50 parts
C H2n + l - I - CH2 C 2 n = ll to 14
O : :
and
50 parts of compo.und A
Test organism Growth inhibition ~ ~
Minimum inhibition concentration ~ ~:
(MIC) in ~ by weight of active :
agent
A B
Trichophyton rubrum O,OQl 0,0025
Microsporum gypseum 0,001 0,0005 ~
~ ~ .
:~
~;-
- 21 - .
54
Example 12
/ C~13
.
CH~ ,
and
B = Mixture of 50 parts
Cn H2n ~ l ~ SO CH2 CH2 n = ll to 14 ,~
and
50 parts of compound A
Test organism Minimum inhibition concentration ;~ :
(MIC) in ~g/ml
A B
Aspergillus niger l00 l00 :~
Candida albicans l00 50
: Example 13
, ~
'
" ,. H3 . ~:
A C13 H27 CO ~ N CE3
CH3
. : t~ournal of the A~lerican Oil Chemist t S Socie-~y,
: 5~, 316-317 (1975)) . . ::
;
.
~ ! ~ 22 ~
.. . ... . . . . . . . ..
~5~54 : `
:
B = Mixture of 50 parts
Cn H2n + 1 ~ SO C~l2 CH2 OH n = 11 to 14 ;~
and ~ ;
50 parts of compound A
Test organ.ism Minimum inhibition concentration
(MIC) in ~g/ml
A B ~:~
Candida albicans 100 50
Staphylococcus aureus 10 10
Saccharomyces cerevisiae10 10 :
~:,,.,; .,
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~ .
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,.................................... ' ~ .
