CN107308453A - 胱氨酸或半胱氨酸的应用、抑菌剂 - Google Patents
胱氨酸或半胱氨酸的应用、抑菌剂 Download PDFInfo
- Publication number
- CN107308453A CN107308453A CN201710525920.9A CN201710525920A CN107308453A CN 107308453 A CN107308453 A CN 107308453A CN 201710525920 A CN201710525920 A CN 201710525920A CN 107308453 A CN107308453 A CN 107308453A
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- Prior art keywords
- cystine
- antibiotic
- bacteriostatic agent
- cysteine
- concentration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 239000000022 bacteriostatic agent Substances 0.000 title claims abstract description 84
- 229960003067 cystine Drugs 0.000 title claims abstract description 71
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 title claims abstract description 69
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 235000018417 cysteine Nutrition 0.000 title claims abstract description 41
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 title claims abstract description 21
- 230000003115 biocidal effect Effects 0.000 claims abstract description 58
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- RDEIXVOBVLKYNT-HDZPSJEVSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-[(1r)-1-aminoethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2 Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)[C@@H](C)N)N)[C@@H](N)C[C@H]1N.O1[C@H]([C@@H](C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-HDZPSJEVSA-N 0.000 claims description 11
- 229960000723 ampicillin Drugs 0.000 claims description 10
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 10
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- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims description 7
- 229930182566 Gentamicin Natural products 0.000 claims description 7
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims description 7
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 claims description 7
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 3
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- 241000894006 Bacteria Species 0.000 abstract description 53
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- 238000001514 detection method Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 description 3
- 241000193830 Bacillus <bacterium> Species 0.000 description 3
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 3
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- 239000000463 material Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
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- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 229960002433 cysteine Drugs 0.000 description 2
- LEVWYRKDKASIDU-IMJSIDKUSA-N cystine group Chemical group C([C@@H](C(=O)O)N)SSC[C@@H](C(=O)O)N LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
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- 229940107700 pyruvic acid Drugs 0.000 description 2
- 238000006479 redox reaction Methods 0.000 description 2
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- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- XBHBWNFJWIASRO-UHFFFAOYSA-N 6-fluoro-1-(4-fluorophenyl)-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1 XBHBWNFJWIASRO-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- DPSPPJIUMHPXMA-UHFFFAOYSA-N 9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid Chemical compound C1CC(C)N2C=C(C(O)=O)C(=O)C3=C2C1=CC(F)=C3 DPSPPJIUMHPXMA-UHFFFAOYSA-N 0.000 description 1
- 241000588624 Acinetobacter calcoaceticus Species 0.000 description 1
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 description 1
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- 229920000832 Cutin Polymers 0.000 description 1
- -1 Dan Nuo Sha Xing Chemical compound 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
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- NOCJXYPHIIZEHN-UHFFFAOYSA-N difloxacin Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1 NOCJXYPHIIZEHN-UHFFFAOYSA-N 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- 150000002466 imines Chemical class 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical class O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
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- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及胱氨酸或半胱氨酸的应用、抑菌剂,属于医药技术领域。本发明发现了胱氨酸或半胱氨酸能够提高抗生素对细菌的有效性,本发明的抑菌剂包括增敏氨基酸和抗生素,将胱氨酸或半胱氨酸和抗生素联用可以提高细菌对抗生素的敏感性,从而克服耐药菌对目的药物的耐药性,从而使抑菌剂更好的发挥杀菌或抑菌活性,为克服细菌耐药提供一种新的解决途径。将胱氨酸或半胱氨酸和抗生素以合适的浓度联用可以显著提高抗生素的杀菌作用,与现有的只用抗生素作为抗菌药物相比,具有更好的效果以及更高的安全性和操作性。
Description
技术领域
本发明涉及胱氨酸或半胱氨酸的应用、抑菌剂,属于医药技术领域。
背景技术
生物体内半胱氨酸可以与胱氨酸相互转化。其实在生物体中起主要作用的是半胱氨酸。半胱氨酸是生物体内一种常见的含硫氨基酸,分子式为C3H7NO2S,溶于水,水中溶解度277.433g/L。溶于稀无机酸和碱性溶液,不易溶于水,难溶于乙醇,不溶于醚和氯仿。半胱氨酸是一种还原剂,可以与发生氧化反应。半胱氨酸在厌氧条件下经脱硫氢酶作用后分解成丙酮酸、硫化氢和氨,或经过转氨基作用,分解为丙酮酸和硫磺。
内源半胱氨酸能在胞内发生氧化还原反应,使细胞的活性增强,而且还能降低或消除有毒物质的活性。半胱氨酸能够有效的治疗放射性伤害。半胱氨酸还有能够分解角质的作用,可作为药物治疗一些皮肤病。由于半胱氨酸在胞内能发生氧化还原反应,具有预防生物体衰老的功能。高水平的内源半胱氨酸对菌体的生长有一定的抑制作用。
病原性细菌严重危害人类身体健康和养殖业的可持续发展。虽然抗生素可以有效进行防治,但抗生素的滥用和误用会导致细菌产生耐药性。细菌耐药后,对原本有效的抗生素产生耐受,导致感染难以控制。因此,采用新的方法控制细菌特别是耐药菌的感染十分重要。一种技术方法是通过提高耐药菌对抗生素的敏感性,使得原本无效或低效的抗生素变得有效,将耐药菌杀死。因此,发现具有提高细菌对抗生素敏感性的分子,将其与抗生素一起制备成复方制剂,对控制细菌特别是耐药菌的感染十分重要。
发明内容
本发明的目的在于提供胱氨酸或半胱氨酸的应用。
本发明的另一个目的在于提供了含增敏氨基酸的抑菌剂,该抑菌剂能提高细菌对抗生素的敏感性,有效抑制细菌的生长。
为了实现上述目的,本发明所采用的技术方案是:
胱氨酸或半胱氨酸的应用,胱氨酸或半胱氨酸在提高抗生素抑菌性能方面的应用。
所述抗生素为喹诺酮类抗生素、氨基糖苷类抗生素、β-内酰胺类抗生素或亚胺培南。
所述喹诺酮类抗生素为诺氟沙星、加替沙星、莫昔沙星、氧氟沙星、环丙沙星、单诺沙星、恩诺沙星、沙拉沙星、二氟沙星、恶喹酸或氟甲喹等。
所述氨基糖苷类抗生素为硫酸庆大霉素、庆大霉素、链霉素、卡那霉素、妥布霉素或阿米卡星等。
所述β-内酰胺类抗生素为青霉素及其衍生物或头孢菌素类抗生素。
所述β-内酰胺类抗生素氨苄青霉素、青霉素或头孢唑林等。
所述喹诺酮类抗生素对大肠杆菌、枸橼酸杆菌、绿脓杆菌、沙雷杆菌、葡萄球菌等有抗菌作用。
所述氨基糖苷类抗生素对铜绿假单胞菌、肺炎杆菌、大肠杆菌等有抗菌作用。
所述β-内酰胺类抗生素对大肠杆菌、克雷伯菌、肠杆菌、吲哚阳性变形杆菌等有抗菌作用。
所述亚胺培南对链球菌、金黄色葡萄球菌、大肠杆菌、克雷伯氏杆菌、不动杆菌部分菌株、流杆嗜血杆菌变形杆菌、沙雷杆菌、绿脓杆菌等有抗菌作用。
本发明发现了胱氨酸及半胱氨酸可以通过调控细菌代谢,改变细菌的耐药性,能够提高细菌及耐药菌对抗生素的敏感性,可以作为抗生素增敏剂使用,可用于提高抗生素的有效性。胱氨酸进入细胞后是转化为半胱氨酸来起作用,半胱氨酸也可直接进入细胞作用。但由于半胱氨酸不够稳定,易被氧化,在实际使用时主要采用胱氨酸。
含增敏氨基酸的抑菌剂,包括增敏氨基酸和抗生素,所述增敏氨基酸为胱氨酸或半胱氨酸,所述增敏氨基酸和抗生素的质量比为24-960:0.05-20。
上述的抑菌剂,所述抗生素为诺氟沙星、硫酸庆大霉素、氨苄青霉素、头孢唑林、亚胺培南、庆大霉素中的一种或几种。
上述的抑菌剂,所述抑菌剂由胱氨酸、诺氟沙星和水组成,胱氨酸的浓度为24-480mg/L,诺氟沙星的浓度为0.05-0.2mg/L。该抑菌剂在实际用于抑制大肠杆菌野生型MG1655和大肠杆菌突变型ZM12时,效果较好。
上述的抑菌剂,胱氨酸的浓度为120-480mg/L,诺氟沙星的浓度为0.05-0.2mg/L。该抑菌剂在实际用于抑制大肠杆菌野生型MG1655和大肠杆菌突变型ZM12时,效果较好。
上述的抑菌剂,所述抑菌剂由胱氨酸、硫酸庆大霉素和水组成,胱氨酸的浓度为120-480mg/L,硫酸庆大霉素的浓度为0.5-2mg/L。该抑菌剂在实际用于抑制大肠杆菌野生型MG1655和大肠杆菌突变型ZM12时,效果较好。
上述的抑菌剂,所述抑菌剂由胱氨酸、硫酸庆大霉素和水组成,胱氨酸的浓度为480mg/L,硫酸庆大霉素的浓度为0.5-2mg/L。该抑菌剂在实际用于抑制大肠杆菌野生型MG1655和大肠杆菌突变型ZM12时,效果较好。
上述的抑菌剂,所述抑菌剂由胱氨酸、氨苄青霉素和水组成,胱氨酸的浓度为120-480mg/L,氨苄青霉素的浓度为5-20mg/L。该抑菌剂在实际用于抑制大肠杆菌野生型MG1655和大肠杆菌突变型ZM12时,效果较好。
上述的抑菌剂,所述抑菌剂由胱氨酸、氨苄青霉素和水组成,胱氨酸的浓度为480mg/L,氨苄青霉素的浓度为5-20mg/L。该抑菌剂在实际用于抑制大肠杆菌野生型MG1655和大肠杆菌突变型ZM12时,效果较好。
上述的抑菌剂,所述抑菌剂由胱氨酸、头孢唑林和水组成,胱氨酸的浓度为0.5mg/L,头孢唑林的浓度为0.5mg/L。该抑菌剂在实际用于抑制肺炎克雷伯杆菌时,效果较好。
上述的抑菌剂,所述抑菌剂由胱氨酸、亚胺培南和水组成,胱氨酸的浓度为0.5mg/L,亚胺培南的浓度为1mg/L。该抑菌剂在实际用于抑制金黄色葡萄球菌时,效果较好。
上述的抑菌剂,所述抑菌剂由胱氨酸、庆大霉素和水组成,胱氨酸的浓度为0.5mg/L,庆大霉素的浓度为1mg/L。该抑菌剂在实际用于抑制奇异变形杆菌时,效果较好。
上述的抑菌剂,所述抑菌剂由半胱氨酸、诺氟沙星和水组成,胱氨酸的浓度为48-960mg/L,诺氟沙星的浓度为0.05-0.2mg/L。该抑菌剂在实际用于抑制大肠杆菌野生型MG1655和大肠杆菌突变型ZM12时,效果较好。
上述的抑菌剂,所述抑菌剂由半胱氨酸、诺氟沙星和水组成,胱氨酸的浓度为960mg/L,诺氟沙星的浓度为0.05-0.2mg/L。该抑菌剂在实际用于抑制大肠杆菌野生型MG1655和大肠杆菌突变型ZM12时,效果较好。
大肠杆菌野生型MG1655和突变型ZM12的来源均是美国伊利诺伊大学JamesA.Imlay教授馈赠。
本发明的抑菌剂包括增敏氨基酸和抗生素,增敏氨基酸为胱氨酸或半胱氨酸,将增敏氨基酸和抗生素联用可以提高细菌对抗生素的敏感性,从而克服耐药菌对目的药物的耐药性,从而使抑菌剂更好的发挥杀菌或抑菌活性,为克服细菌耐药提供一种新的解决途径。将增敏氨基酸和抗生素以合适的浓度联用可以显著提高抗生素的杀菌作用,与现有的只用抗生素作为抗菌药物相比,具有更好的效果以及更高的安全性和操作性。本发明的抑菌剂在使用时能够较少抗生素的用量,既能较好的抑制细菌的生长,还能防止滥用抗生素导致的耐药菌株增多、耐药性性增强。
附图说明
图1为试验例1中单独胱氨酸对大肠杆菌的抑制效果图;
图2为试验例1中单独半胱氨酸对大肠杆菌的抑制效果图;
图3为试验例2中各抑菌剂对大肠杆菌的抑制效果图;
图4为试验例3中各抑菌剂对大肠杆菌的抑制效果图;
图5为试验例4中各抑菌剂对大肠杆菌的抑制效果图;
图6为试验例5中各抑菌剂对大肠杆菌的抑制效果图;
图7为试验例6中各抑菌剂对菌的抑制效果图。
具体实施方式
下面结合具体实施例对本发明做进一步的详细说明。
以下实施例及试验例中大肠杆菌野生型MG1655和突变型ZM12的来源均是美国伊利诺伊大学James A.Imlay教授馈赠。
下述实施例及试验例所使用的实验方法若无特殊说明,均为本技术领域现有常规的方法,所使用的配料或材料,如无特殊说明,均为通过商业途径可得到的配料或材料。
实施例1
本实施例中的含增敏氨基酸的抑菌剂由胱氨酸、诺氟沙星、水组成,胱氨酸的浓度为120mg/L,诺氟沙星的浓度为0.05mg/L。
实施例1-36中的胱氨酸抑菌剂由胱氨酸、抗生素、水组成,胱氨酸及抗生素的浓度如表1所示。
表1 实施例1-36中的抑菌剂组成
实施例37-39中的含增敏氨基酸抑菌剂由胱氨酸、抗生素、水组成,胱氨酸和抗生素的浓度如表2所示。
表2 实施例37-39中的抑菌剂组成
胱氨酸(mg/L) | 头孢唑林(mg/L) | 亚胺培南(mg/L) | 庆大霉素(mg/L) | |
实施例37 | 0.5 | 0.5 | ||
实施例38 | 0.5 | 1 | ||
实施例39 | 0.5 | 1 |
实施例40-54中的含增敏氨基酸抑菌剂由半胱氨酸、抗生素、水组成,半胱氨酸和抗生素的浓度如表3所示。
表3 实施例40-54中的抑菌剂组成
半胱氨酸(mg/L) | 诺氟沙星(mg/L) | |
实施例40 | 48 | 0.05 |
实施例41 | 48 | 0.1 |
实施例42 | 48 | 0.2 |
实施例43 | 96 | 0.05 |
实施例44 | 96 | 0.1 |
实施例45 | 96 | 0.2 |
实施例46 | 240 | 0.05 |
实施例47 | 240 | 0.1 |
实施例48 | 240 | 0.2 |
实施例49 | 480 | 0.05 |
实施例50 | 480 | 0.1 |
实施例51 | 480 | 0.2 |
实施例52 | 960 | 0.05 |
实施例53 | 960 | 0.1 |
实施例54 | 960 | 0.2 |
对比例1
本对比例中的抑菌剂为0.05mg/L的诺氟沙星水溶液。
对比例1-11中的抑菌剂为抗生素水溶液,抗生素的种类及浓度如表4所示。对比例7为无菌水,不含有抗生素。
表4 对比例1-11中的抑菌剂成分
对比例14-29中抑菌剂为胱氨酸或半胱氨酸,其浓度如表5所示。
表5 对比例14-29中的抑菌剂成分
试验例1
细菌样品的制备:挑取大肠杆菌MG1655的菌落分别于30ml的LB液体培养基中,37℃摇床培养至饱和。然后在接种到贫硫培养基中培养4h左右,将其稀释到菌体值OD600=0.2,吸取菌液至25ml锥形瓶中备用。
取OD600=0.2左右的大肠杆菌野生型MG1655的菌液1mL于试管中,然后加入对比例14-29中的胱氨酸或半胱氨酸水溶液,于37℃恒温培养17h左右。用液体培养的方法,通过检测菌量增长状况(OD600)检测对比例14-29对于大肠杆菌MG1655的抑制情况。
对比例14-21的结果如图1所示,对比例22-29的结果如图2所示,纵坐标为胱氨酸或半胱氨酸的浓度,单位为mg/L;结果表明在胱氨酸或者半胱氨酸的单独作用下,随着胱氨酸或半胱氨酸浓度的增大,其对大肠杆菌的生长基本上没有抑制作用。
试验例2
细菌样品的制备:挑取大肠杆菌ZM12的菌落分别于30ml的LB液体培养基中,37℃摇床培养至饱和。然后在接种到贫硫培养基中培养4h左右,将其稀释到菌体值OD600=0.2,吸取菌液至25ml锥形瓶中备用。
取OD600=0.2左右的大肠杆菌ZM12的菌液1mL于试管中,然后加入实施例16-24及对比例4-6、对比例7、14、16、17的抑菌剂,于37℃恒温培养17h左右。用液体培养的方法,通过检测菌量增长状况(OD600)检测实施例16-24及对比例4-6、对比例7、14、16、17中的抑菌剂对于大肠杆菌ZM12的抑制情况。
结果如图3所示,图3中从左至右是对比例7、对比例4-6;对比例14、实施例16-18;对比例16,实施例19-21;对比例17,实施例22-24,从图中可以看出当胱氨酸浓度恒定的情况下,与硫酸庆大霉素联用时可显著抑制细菌的生长状况,均可提高细菌多种抗生素的敏感性。但当胱氨酸的浓度逐渐增大时,可基本上抑制细菌的生长。
试验例3
按照试验例1的方法制备大肠杆菌MG1655菌液样品。
取OD600=0.2左右的大肠杆菌野生型MG1655的菌液1mL于试管中,然后加入实施例19-27、7-15、28-36及对比例1-3、4-6、7-10的抑菌剂,于37℃恒温培养17h左右。用液体培养的方法,通过检测菌量增长状况(OD600)检测实施例19-27、7-15、28-36及对比例1-3、4-6、7-10中的抑菌剂对于大肠杆菌MG1655的抑制情况。
结果如图4所示。图4中从左至右依次是对比例7、对比例4-6、对比例1-3、对比例8-10;对比例16、实施例19-21、实施例7-9、实施例28-30;对比例17、实施例22-24、实施例10-12、实施例31-33;对比例18、实施例25-27、实施例13-15、实施例34-36,从图4中可以看出在胱氨酸浓度恒定的情况下,与诺氟沙星、氨苄青霉素、硫酸庆大霉素联用时均可显著抑制细菌的生长状况,均可提高细菌对多种抗生素的敏感性。但当胱氨酸的浓度逐渐增大时,可基本上抑制细菌的生长。
试验例4
按照试验例1的方法制备大肠杆菌MG1655菌液样品。
取OD600=0.2左右的大肠杆菌野生型MG1655的菌液1mL于试管中,然后加入实施例1-15及对比例7、对比例1-3、14-18的抑菌剂,于37℃恒温培养17h左右。用液体培养的方法,通过检测菌量增长状况(OD600)检测实施例1-15及对比例1-3、14-18的抑菌剂对于大肠杆菌MG1655的抑制情况。
结果如图5所示,图5从左至右分别是对比例7、对比例1-3;对比例14、实施例1-3;对比例15、实施例4-6;对比例16、实施例7-9;对比例17、实施例10-12;对比例18、实施例13-15,从图5中可以看出当胱氨酸在较低浓度下时,诺氟沙星抗生素与胱氨酸联用时能够促进细菌的生长,但是当胱氨酸与抗生素的浓度同时增大时,诺氟沙星与胱氨酸联用时能够显著降低细菌的生长。因此胱氨酸与抗生素联用能够提高细菌对抗生素的敏感性,且具有浓度依赖性。
试验例5
按照试验例1的方法制备大肠杆菌MG1655菌液样品。
取OD600=0.2左右的大肠杆菌野生型MG1655的菌液1mL于试管中,然后加入实施例40-54及对比例7、对比例1-3、22-29的抑菌剂,于37℃恒温培养17h左右。用液体培养的方法,通过检测菌量增长状况(OD600)检测实施例40-54及对比例1-3、22-29中的抑菌剂对于大肠杆菌MG1655的抑制情况。
结果如6所示,图6从左至右分别是对比例7、对比例1-3;对比例22、实施例40-42;对比例23、实施例43-45;对比例24、实施例46-48;对比例25、实施例49-51;对比例26、实施例52-54,从图6中可以看出当胱氨酸在较低浓度下时,诺氟沙星抗生素与半胱氨酸联用时能够促进细菌的生长,但是当半胱氨酸与抗生素的浓度同时增大时,诺氟沙星与半胱氨酸联用时能够显著降低细菌的生长。因此半胱氨酸与抗生素联用能够提高细菌对抗生素的敏感性,且具有浓度依赖性。
试验例6
按照试验例1的方法制备肺炎克雷伯杆菌、金黄色葡萄菌、奇异变形杆菌的菌液样品。
1、取稀释后的肺炎克雷伯杆菌稀释液OD600=0.2左右的菌液1ml于试管中,然后依次分加入实施例37及对比例7、11中的抑菌剂,于37℃恒温培养17h左右。用液体培养的方法,通过检测菌量增长状况(OD600)检测实施例37及对比例7、11中的抑菌剂对于肺炎克雷伯杆菌的抑制情况。
2、取稀释后的金黄色葡萄菌稀释液OD600=0.2左右的菌液1ml于试管中,然后依次分加入实施例38及对比例7、12中的抑菌剂,于37℃恒温培养17h左右。用液体培养的方法,通过检测菌量增长状况(OD600)检测实施例38及对比例7、12中的抑菌剂对于金黄色葡萄菌的抑制情况。
3、取稀释后的奇异变形杆菌稀释液OD600=0.2左右的菌液1ml于试管中,然后依次分加入实施例39及对比例7、13中的抑菌剂,于37℃恒温培养17h左右。用液体培养的方法,通过检测菌量增长状况(OD600)检测实施例39及对比例7、13中的抑菌剂对于奇异变形杆菌的抑制情况。
结果如图7所示。图7从左至右依次是,对比例7、对比例11、实施例37;对比例7、对比例12、实施例38;对比例7、对比例13、实施例39,从图7中可以看出:对于肺炎克雷伯杆菌而言,在抗生素头孢唑林浓度一定的情况下,与胱氨酸联用时,可明显抑制肺炎克雷伯杆菌的生长;对于金黄色葡萄菌而言在抗生素亚胺培南浓度一定的情况下,与胱氨酸联用时可明显抑制金黄色葡萄菌的生长;对于奇异变形杆菌而言,在抗生素庆大霉素浓度一定的情况下,与胱氨酸联用时可明显抑制奇异变形杆菌的生长。
Claims (9)
1.胱氨酸或半胱氨酸的应用,其特征在于:胱氨酸或半胱氨酸在提高抗生素抑菌性能方面的应用。
2.根据权利要求1所述的应用,其特征在于:所述抗生素为喹诺酮类抗生素、氨基糖苷类抗生素、β-内酰胺类抗生素或亚胺培南。
3.根据权利要求1所述的应用,其特征在于:所述β-内酰胺类抗生素为青霉素及其衍生物或头孢菌素类抗生素。
4.含增敏氨基酸的抑菌剂,其特征在于:包括增敏氨基酸和抗生素,所述增敏氨基酸为胱氨酸或半胱氨酸,所述增敏氨基酸和抗生素的质量比为24-960:0.05-20。
5.根据权利要求4所述的抑菌剂,其特征在于:所述抗生素为诺氟沙星、硫酸庆大霉素、氨苄青霉素、头孢唑林、亚胺培南、庆大霉素中的一种或几种。
6.根据权利要求4所述的抑菌剂,其特征在于:所述抑菌剂由胱氨酸、诺氟沙星和水组成,胱氨酸的浓度为24-480mg/L,诺氟沙星的浓度为0.05-2mg/L。
7.根据权利要求4所述的抑菌剂,其特征在于:所述抑菌剂由胱氨酸、硫酸庆大霉素和水组成,胱氨酸的浓度为120-480mg/L,硫酸庆大霉素的浓度为0.5-2mg/L。
8.根据权利要求4所述的抑菌剂,其特征在于:所述抑菌剂由胱氨酸、氨苄青霉素和水组成,胱氨酸的浓度为120-480mg/L,氨苄青霉素的浓度为5-20mg/L。
9.根据权利要求4所述的抑菌剂,其特征在于:所述抑菌剂由半胱氨酸、诺氟沙星和水组成,胱氨酸的浓度为48-960mg/L,诺氟沙星的浓度为0.05-0.2mg/L。
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