CN102370633A - Bacterial YycG histidine kinase inhibitor - Google Patents

Bacterial YycG histidine kinase inhibitor Download PDF

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CN102370633A
CN102370633A CN2010102574411A CN201010257441A CN102370633A CN 102370633 A CN102370633 A CN 102370633A CN 2010102574411 A CN2010102574411 A CN 2010102574411A CN 201010257441 A CN201010257441 A CN 201010257441A CN 102370633 A CN102370633 A CN 102370633A
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yycg
histidine kinase
kinase inhibitor
micromolecular compound
staphylococcus epidermidis
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瞿涤
蒋华良
沈旭
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Fudan University
Shanghai Institute of Materia Medica of CAS
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Fudan University
Shanghai Institute of Materia Medica of CAS
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Abstract

The invention, belonging to the technical field of biology, relates to a bacterial inhibitor, particularly relates to a bacterial YycG histidine kinase inhibitor containing micro-molecular compound 4-methyl-3-(5-(2-(naphtho [2,1-b]furyl) acetamido)amino methylene-2-furyl)phenylacetic acid, especially an inhibitor of the signal transduction system YycG protein of gram-positive bacteria. The bacterial YycG histidine kinase inhibitor disclosed herein has inhibiting effect on YycG protein in a staphylococcus epidermidis signal transduction system, can inhibit the growth of gram-positive bacteria and inhibit the biofilm formation of staphylococcus epidermidis. The inhibitor can be used for preparing medicines for treating diseases caused by gram-positive bacteria, and can be prepared into disinfectant for medical instruments or medical implements.

Description

A kind of antibacterial YycG histidine kinase inhibitor
Technical field
The invention belongs to biological technical field, relate to bacterial inhibitor, be specifically related to a kind of antibacterial YycG histidine kinase inhibitor, especially to the proteic inhibitor of signal transduction system YycG of gram positive bacteria.Antibacterial YycG histidine kinase inhibitor of the present invention, inhibited to YyCG albumen in the staphylococcus epidermidis signal transduction system, can suppress the gram-positive cocci growth, and suppress the biomembranous formation of staphylococcus.
Background technology
Staphylococcus epidermidis ATCC12228 and ATCC35984 bacterial strain to genome sequencing are analyzed, and find that it has 16 or 17 pairs of bi-component signal transduction systems.The bi-component signal transduction system mainly is present in various prokaryotes, various biological functions such as regulation and control biological growth, virulence, and fail to find to have homologous protein in the eukaryotic cell.The bi-component signal transduction system of antibacterial comprises Histidine kinase and reaction adjusting albumen, and Histidine kinase activates after receiving environmental stimuli, signal is passed on learn active to downstream albumen with the associated biomolecule of regulation and control antibacterial.We have carried out the protein structure three-dimensional simulation to the YycG albumen in the staphylococcus epidermidis bi-component signal transduction system (YycG Histidine kinase); And according to this model; It is virtual to utilize butt joint software to carry out, and acquisition can suppress gram-positive bacteria growth such as staphylococcus epidermidis and suppress biological film formed micromolecule mortifier.
S. epidernidisBecome the main factor that nosocomial infection takes place in the transplant operation.In addition, owing to antibiotic abuse, S. epidernidis of more serious multiresistance and anti-vancocin has appearred.And S. epidernidisThe main cause that develops immunity to drugs is the biomembrane attached to the antibacterial of medical apparatus surface secretion protectiveness, and this biomembrane can hinder traditional antibiotic and pass and act on antibacterial, the performance bactericidal effect.Except on the medical apparatus and instruments S. epidernidis,Infection host is intravital S. epidernidisExcretory biomembrane can hinder the attack of host immune system.Therefore specificity has disrupting biofilm and in the performance bactericidal action, has prospect widely with the new antibiotic that kills and wounds antibacterial.
Summary of the invention
The purpose of this invention is to provide a kind of antibacterial YycG histidine kinase inhibitor, especially to the proteic inhibitor of signal transduction system YycG of gram positive bacteria.Gram positive bacteria of the present invention comprises clinical common GPC, like staphylococcus epidermidis, staphylococcus aureus or micrococcus scarlatinae.
Antibacterial YycG histidine kinase inhibitor of the present invention; It is characterized in that; Form by micromolecular compound 4-methyl-3-(5-(2-(naphtho-[2,1-b] furan) acetamido) aminomethylene-2-furyl) phenylacetic acid (being called for short FKK051103-51) of formula I structure and the DMSO (dimethyl sulfoxine) of 0.1-2%.
Figure 700009DEST_PATH_IMAGE001
（Ⅰ）
Micromolecular compound of the present invention FKK051103-51 hasDisrupting biofilm and the dual-use function that kills and wounds antibacterial can effectively suppress several kinds of clinical common GPC growths and suppress the biomembranous formation of staphylococcus epidermidis, and mammalian cell is not had overt toxicity.。
Micromolecular compound of the present invention FKK051103-51Can obtain through commercial (Dutch SPECS).
The present invention adopts minimal inhibitory concentration test, micro-bacterial biof iotalm to detect methods such as test, enzyme inhibition test alive, MTT test, has detected bacteriostatic activity, antibiont film activity, enzyme inhibition activity and the cytotoxicity of said micromolecular compound.
The standard tube dilution method of recommending with the NCCLS (the National Committee for Clinical Laboratory Standards) of the U.S. detects the minimal inhibitory concentration (MIC) of micromolecular compound.The result shows that this micromolecular compound can obviously suppress several kinds of clinical common GPC growths (staphylococcus epidermidis, staphylococcus aureus, micrococcus scarlatinae), and is as shown in table 1.
Adopt micro-bacterial biof iotalm to detect test (96 orifice plate biomembranes form test) and carry out the detection of antibiont film activity; Forming positive strain ATCC35984 with the staphylococcus epidermidis biomembrane (purchases in US mode and cultivates the collection warehousing as test strain; American type culture collection); Micromolecular compound connect with antibacterial mix (final concentration 200 μ M), be inoculated on 96 orifice plates, cultivate the back and in the hole, forms biomembranous power (violet staining judgement) according to antibacterial.The result shows that this micromolecular compound can obviously suppress the biomembranous formation of staphylococcus epidermidis, compares with the matched group that does not add chemical compound and reduces biomembrane formation more than 30%, and is as shown in table 2.
Detect the toxic action of micromolecular compound with mtt assay to mammalian cell; This micromolecular compound of presentation of results to the half suppression ratio of Vero cell growth more than 200 μ M; Is 2% at this micromolecular compound of minimal inhibitory concentration to the growth inhibition ratio of Vero cell; Have basically no toxicity, as shown in table 3.
Detect the haemolysis of micromolecular compound to the HRBC with 96 well plate method, this micromolecular compound of presentation of results and destination protein staphylococcus epidermidis histidine kinase YycG are conservative, and the functional domain fragment has very strong adhesion (binding equilibrium constant K D＜10 -5M, and the active (half-inhibition concentration＜50 μ M of the autophosphorylation of the obvious CKIs histidine kinase YycG of ability.
The present invention has following advantage:
1. micromolecular compound FKK051103-51The biomembranous formation of staphylococcus epidermidis can be obviously suppressed, the growth of several kinds of clinical common GPCs can be significantly suppressed simultaneously.
2. this micromolecular compound has disrupting biofilm and the dual-use function that kills and wounds antibacterial.
3. this micromolecular compound to the basic avirulence of mammalian cell, and does not have tangible haemolysis to the HRBC when minimal inhibitory concentration.
4. the conservative functional domain fragment of this micromolecular compound and destination protein staphylococcus epidermidis histidine kinase YycG has very strong adhesion, and the autophosphorylation of the obvious CKIs histidine kinase YycG of ability is active.
Micromolecular compound of the present invention can prepare antibacterial YycG histidine kinase inhibitor.
Micromolecular compound of the present invention can prepare medical apparatus and instruments or medical apparatus disinfectant solution.
Micromolecular compound of the present invention can further carry out the transformation of chemical constitution, prepares the novel drugs that anti-GPC catches.
Description of drawings
Fig. 1 is the haemolysis result of micromolecular compound FKK051103-51 to the HRBC,
Wherein, with the negative contrast of 1%DMSO+ erythrocyte, the positive contrast of 1% cell-penetrating liquid Triton-100+ cell; The MIC value of micromolecular compound is 4 μ g/ml; Tet: tetracycline, its MIC value of list of references report is got 0.3 μ g/ml; Cip: ciprofloxacin, its MIC value of list of references report is got 0.25 μ g/ml;
Fig. 1 has shown that this micromolecular compound when minimal inhibitory concentration (MIC) and 4 times of MIC concentration, does not have tangible haemolysis to the HRBC.
The specific embodiment
Below in conjunction with experimental example the present invention is described in further detail but do not limit the present invention.
The minimal inhibitory concentration of embodiment 1 FKK051087-51 detects
The standard tube dilution method of recommending with the NCCLS (the National Committee for Clinical Laboratory Standards) of the U.S. detects the minimal inhibitory concentration (MIC) of micromolecular compound, and experimental technique is following:
1. microbionation is in fresh MH culture medium, 37 ℃ of overnight incubation.
2. liquid 1:100 is inoculated in fresh MH culture medium, and 37 ℃ to be cultured to logarithmic growth early stage, is diluted to OD with fresh MH culture medium 600=, every pipe 1ml, the micromolecular compound (solvent DMSO final concentration keeps 1%) of adding variable concentrations gradient was cultivated 18 hours for 37 ℃.Because of micromolecular compound is dissolved among the DMSO, therefore establish the 1%DMSO+ antibacterial for contrast, be blank with the aseptic culture medium.
3. compare with blank, the pipe that the concentration that antibacterial does not grow is minimum is the minimal inhibitory concentration of this micromolecular compound.
The result shows that growth has the obvious suppression effect to this micromolecular compound to several kinds of clinical common GPCs (staphylococcus epidermidis, staphylococcus aureus, micrococcus scarlatinae), and is as shown in table 1.
The inhibitory action that table 1 micromolecular compound FKK051103-51 grows to several kinds of clinical common GPCs
Figure 763648DEST_PATH_IMAGE002
Embodiment 2 FKK051087-51 suppress the biomembranous formation of staphylococcus epidermidis
Adopt micro-bacterial biof iotalm to detect test (96 orifice plate biomembranes form test); The staphylococcus epidermidis biomembrane is formed positive strain ATCC35984 mix (final concentration 200 μ M) with micromolecular compound, be inoculated on 96 orifice plates, form the negative contrast of negative strain ATCC12228 with the staphylococcus epidermidis biomembrane simultaneously; Cultivate after 20 hours for 37 ℃; Antibacterial forms biomembrane and can detect with crystal violet staining assay in the hole, after the violet staining washing, according to OD 570Reading judges that bacterial biof iotalm forms the power of situation.Experimental technique is following:
1. staphylococcus epidermidis is inoculated in the fresh TSB culture medium, 37 ℃ of overnight incubation.
2. bacterium 1:200 is inoculated in 96 orifice plates with fresh TSB culture medium dilution, every hole 200 μ l, and 37 ℃ left standstill cultivation after 6 hours, added micromolecular compound (final concentration 200 μ M, solvent DMSO final concentration is 1%), appearance on each samples using three multiple hole.Because of micromolecular compound is dissolved among the DMSO, therefore establish the positive contrast of 1%DMSO+ staphylococcus epidermidis biofilm positive strain, establish the negative contrast of 1%DMSO+ staphylococcus epidermidis biofilm negative strain.
3. bacterium liquid is washed plate 3 times with PBS, dries, and every hole adds 200 μ l, 2% crystal violet room temperature dyeing 5 minutes.
4. unnecessary dye liquor dries plate, ELIASA OD 570Reading, each sample reading are got the average in three multiple holes.
5. micromolecular compound is to the biomembranous suppression ratio of staphylococcus epidermidis:
Positive control OD 570Average-sample OD 570Average
Figure 900625DEST_PATH_IMAGE003
×100％
Positive control OD 570Average
This micromolecular compound of presentation of results can obviously suppress the biomembranous formation of staphylococcus epidermidis external, compares with the positive control that does not add chemical compound, can reduce biomembrane and form more than 30%, and is as shown in table 2.
Table 2 micromolecular compound FKK051103-51 is to the biological film formed influence of staphylococcus epidermidis
Micromolecular compound OD 570 The OD value (X ± S)
FKK051103-51 0.062±0.004
Positive control a 1.702±0.069
Negative control b 0.200±0.022
aPositive control refers to that 1%DMSO+ staphylococcus epidermidis biomembrane forms positive strain
bNegative control refers to that 1%DMSO+ staphylococcus epidermidis biomembrane forms negative strain
The cytotoxicity of embodiment 3 FKK051087-51 detects
Detect the toxic action of micromolecular compound to mammalian cell with mtt assay, experimental technique is following:
1. the Vero cell inoculation of fresh cultured is in 96 orifice plates, every hole 100ul cell (about 5 * 10 4Cell), 37 ℃, 5%CO 2Cultivated 24 hours under the condition, make cell grow up to monolayer.
2. go culture medium, add the fresh MEM culture medium in the every hole of 100ul/, wherein contain the micromolecular compound (solvent DMSO final concentration keeps 1%) of variable concentrations, appearance on each samples using four multiple hole, 37 ℃, 5%CO 2Continue under the condition to cultivate 24 hours.Because of micromolecular compound is dissolved among the DMSO, therefore establishes the 1%DMSO+ cell and be contrast.
3. add 10ul MTT label, 37 ℃, 5%CO 2Cultivated 4 hours under the condition.
4.6 taking out, orifice plate reads OD 570Value, each sample reading are got the average in four multiple holes, calculate the suppression ratio of the micromolecular compound of variable concentrations to the growth of Vero cell:
Contrast OD 570Average-sample OD 570Average
Figure 980708DEST_PATH_IMAGE003
×100％
Contrast OD 570Average
Half amount of suppression IC 50Value adopts the Logit method to calculate.
Presentation of results is at cellular level, and the half suppression ratio of this micromolecular compound is more than 200 μ M, and the growth inhibition ratio to the Vero cell when minimal inhibitory concentration is 1%, does not have toxicity basically, and is as shown in table 3.
Table 3 micromolecular compound FKK051103-51 is to the toxic action of Vero cell
Micromolecular compound Half suppression ratio (IC 50 ，μM） Suppression ratio during minimal inhibitory concentration
FKK051103-51 >;200 2% (4μg/ml) a
aBe that micromolecular compound FKK051103-51 is to the staphylococcic minimal inhibitory concentration of epidermis in the bracket
Embodiment 4 FKK051087-51 combine and suppress phosphorylation with destination protein
Utilize the energy resonance bio-sensing chip to detect FKK051087-52 and the conservative segmental adhesion of functional domain of staphylococcus epidermidis histidine kinase YycG; Use Kinase-Glo TMLuminescent Kinase Assay Kit detects the effect of enzyme work and FKK051087-52 inhibitory enzyme activity, and experimental technique is following:
1. the conservative functional domain fragment of destination protein staphylococcus epidermidis histidine kinase YycG recombinant expressed, purification is coupled on the energy resonance bio-sensing chip (Biacore CM5 cake core); Micromolecular compound to be measured is pressed certain gradient dilution; Let it flow through chip and protein-interacting; Observe micromolecular compound and protein bound situation, calculate the binding equilibrium constant K D
2. micromolecular compound suppresses the Kinase-Glo of the experiment of histidine kinase YycG autophosphorylation with U.S. PROMEGA company TM(Madison USA) accomplishes Luminescent Kinase Assay Kit for Cat. No.V6711, Promega.The micromolecular compound of conservative functional domain fragment of destination protein histidine kinase YycG 4 μ g are recombinant expressed, purification and gradient dilution was 25 ℃ of effects 20 minutes; Add 100 μ M ATP (reaction cumulative volume 50ul) then and after 20 minutes reactant mixture is added 96 hole ELISA Plates 25 ℃ of effects; Every hole 50ul adds Kinase-Glo TMThe every hole of Reagent 50 ul room temperatures left standstill 10 minutes, read the amount of chemiluminescence value representation reaction residual A TP, and experiment establishes that not add the micromolecular compound group be matched group.Be calculated as follows the suppression ratio of micromolecular compound at last to the destination protein phosphorylation:
(the group of albumen+micromolecule+Reagent) chemiluminescence average-(the group chemiluminescence average of albumen+Reagent)
×100％
(Reagent) group chemiluminescence average-(albumen+Reagent) chemiluminescence average
Half-inhibition concentration IC 50Value adopts the Logit method to calculate.
This micromolecular compound of presentation of results and destination protein staphylococcus epidermidis histidine kinase YycG are conservative, and the functional domain fragment has very strong adhesion (binding equilibrium constant K D＜10 -5M), and the autophosphorylation activity of the obvious CKIs histidine kinase YycG of ability (half-inhibition concentration＜50 μ M, as shown in table 4.
The effect of the adhesion of table 4. FKK051103-51 and destination protein and inhibition phosphorylation
Micromolecular compound K D Value (μ M) a IC 50 Value (μ M) b
FKK051103-51 2.8 13.5
aK DOn behalf of micromolecular compound and destination protein staphylococcus epidermidis histidine kinase YycG, value guard functional domain fragment adhesion for the binding equilibrium constant, and the more little expression adhesion of its value is strong more
bIC 50Value is a half-inhibition concentration, represents the concentration when half histidine kinase YycG guards functional domain fragment autophosphorylation in the micromolecular compound inhibitory reaction system.
 
Embodiment 5 FKK051087-51 are to HRBC's haemolysis
Detect the haemolysis of micromolecular compound to the HRBC with 96 well plate method, concrete process of the test is following:
1. isolating healthy subjects erythrocyte is washed 3 times with physiological saline solution, and is diluted to 5%.
2. in 5% red cell suspension, every hole 200ul is inoculated on 96 orifice plates micromolecular compound of variable concentrations (solvent DMSO final concentration keeps 1%), each samples using three multiple hole.Because of micromolecular compound is dissolved among the DMSO, therefore establish the negative contrast of 1%DMSO+ cell, establish the positive contrast of 1% cell-penetrating liquid Triton-100+ cell, and establish two kinds of common antibiotics tetracyclines and ciprofloxacin compares.
3. put 37 ℃ of incubators and cultivated 1 hour, get the 100ul supernatant after centrifugal to move into 96 clean orifice plates of another piece, OD 570Reading, each sample reading are got the average in three multiple holes.
Presentation of results is compared with negative control, positive control and two kinds of common antibiotics contrasts, and this micromolecular compound does not have obvious haemolysis to the HRBC when minimal inhibitory concentration (MIC) and 4 times of MIC concentration, as shown in Figure 1.

Claims (7)

1. antibacterial YycG histidine kinase inhibitor; It is characterized in that; Form by micromolecular compound 4-methyl-3-(5-(2-(naphtho-[2,1-b] furan) acetamido) aminomethylene-2-furyl) phenylacetic acid of formula I structure and the xylene maple of 0.1-2%
Figure 2010102574411100001DEST_PATH_IMAGE001
（ Ⅰ） 。
2. by the described antibacterial YycG of claim 1 histidine kinase inhibitor, it is characterized in that described antibacterial is a gram-positive cocci.
3. by claim 1 or 2 described antibacterial YycG histidine kinase inhibitor, it is characterized in that described antibacterial is staphylococcus epidermidis, staphylococcus aureus or micrococcus scarlatinae.
4. the described antibacterial YycG of claim 1 histidine kinase inhibitor suppresses the purposes in the gram-positive cocci growth preparation in preparation.
5. the described antibacterial YycG of claim 1 histidine kinase inhibitor suppresses the purposes in the staphylococcus biomembrane formation preparation in preparation.
6. the described antibacterial YycG of claim 1 histidine kinase inhibitor is used in the medicine of the disease that the preparation treatment is caused by gram-positive cocci.
7. by the described antibacterial YycG of claim 1 histidine kinase inhibitor, it is characterized in that described inhibitor is mixed with medical apparatus and instruments or medical apparatus disinfectant solution.
CN2010102574411A 2010-08-19 2010-08-19 Bacterial YycG histidine kinase inhibitor Pending CN102370633A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10130867B2 (en) 2012-10-23 2018-11-20 Angel Playing Cards Co., Ltd. Table game system
CN113952339A (en) * 2020-07-21 2022-01-21 复旦大学 Use of compound FDEFA1 in preparation of gram-positive cocci inhibitor

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1875956A (en) * 2005-06-10 2006-12-13 复旦大学 Inhibitor for YycG protein of staphylococcus epidermidis signal transduction system

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1875956A (en) * 2005-06-10 2006-12-13 复旦大学 Inhibitor for YycG protein of staphylococcus epidermidis signal transduction system

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
STN数据库: "STN数据库中关于化合物4-甲基-3-（5-（2-（萘并[2,1-b]呋喃）乙酰胺基）氨基亚甲基-2-呋喃基）苯乙酸的记录", 《STN数据库》 *
ZHIQIANG QIN,ET AL.: "Structure-based discovery of inhibitors of the YycG histidine kinase：New chemical leads to combat Staphylococcus epidermidis infections", 《BMC MICROBIOLOGY》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10130867B2 (en) 2012-10-23 2018-11-20 Angel Playing Cards Co., Ltd. Table game system
CN113952339A (en) * 2020-07-21 2022-01-21 复旦大学 Use of compound FDEFA1 in preparation of gram-positive cocci inhibitor
CN113952339B (en) * 2020-07-21 2023-12-26 复旦大学 Use of compound FDEFA1 in preparation of gram-positive coccus inhibitor

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