WO2021109292A1 - 金化合物在制备抗菌剂中的应用 - Google Patents

金化合物在制备抗菌剂中的应用 Download PDF

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WO2021109292A1
WO2021109292A1 PCT/CN2019/128968 CN2019128968W WO2021109292A1 WO 2021109292 A1 WO2021109292 A1 WO 2021109292A1 CN 2019128968 W CN2019128968 W CN 2019128968W WO 2021109292 A1 WO2021109292 A1 WO 2021109292A1
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bacteria
gram
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杨亮
刘玉梅
刘洋
韩舒虹
刘晓璇
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南方科技大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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  • the invention relates to the technical field of antibacterial agents, in particular to the application of a class of gold compounds in the preparation of antibacterial agents.
  • the World Health Organization issued a report saying that the current development of new antibiotics is seriously insufficient to combat the growing threat of antimicrobial resistance.
  • the report also identified 12 key pathogens. These pathogenic microorganisms are increasingly resistant to existing antibiotics, and new therapeutic drugs are urgently needed.
  • These 12 key pathogens include six drug-resistant bacteria ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa And Enterobacter spp.).
  • the six drug-resistant bacteria are widely distributed in the natural environment. They are important pathogens that cause hospital infections. They are common pathogens in hospitalized patients, especially patients with low immunity in intensive care units.
  • the present invention aims to solve at least one of the technical problems existing in the prior art. For this reason, the present invention proposes the application of a class of gold compounds in the preparation of antibacterial agents.
  • the first aspect of the present invention provides the use of a class of compounds or their pharmaceutically acceptable salts in the preparation of antibacterial agents.
  • the compounds have the following structural formula:
  • R 1 to R 3 are independently selected from C1-C6 alkyl, C1-C6 alkoxy and aryl; X 1 is halogen.
  • the compound provided by the present invention can quickly and effectively kill germs at a lower concentration, thereby achieving a better antibacterial effect.
  • R 1 to R 3 are each independently selected from a C1-C6 alkyl group, a C1-C6 alkoxy group, and a phenyl group.
  • R 1 to R 3 are each independently selected from a C1-C3 alkyl group, a C1-C3 alkoxy group, and a phenyl group.
  • the number of phenyl groups in R 1 to R 3 does not exceed one.
  • R 1 to R 3 are each independently selected from a methyl group, an ethyl group, a methoxy group, and an ethoxy group.
  • X 1 is selected from F, Cl, Br, and I.
  • X 1 is Cl.
  • the compound is selected from:
  • the compound is selected from:
  • the antibacterial agent is used to prevent and/or treat bacterial infections, and the bacteria are Gram-positive bacteria or Gram-negative bacteria.
  • the gram-positive bacteria are selected from bacteria of the genus Staphylococcus and Enterococcus; the gram-negative bacteria are selected from the genus Acinetobacter, Pseudomonas, Escherichia, and Bacteria of the genus Leberella, Salmonella, and Vibrio.
  • the gram-positive bacteria are selected from Staphylococcus aureus, Enterococcus Faecium; the gram-negative bacteria are selected from Acinetobacter baumannii, aureus Pseudomonas aeruginosa, Escherichia coli, Klebsiella Pneumoniae, Salmonella enteriditis, Vibrio cholerae.
  • Fig. 1 is a bactericidal curve of a compound of an embodiment of the present invention against the strain A. baumannii 53264 of Acinetobacter baumannii.
  • Fig. 2 is a bactericidal curve of a compound of an embodiment of the present invention against the strain A. baumannii ACICU of Acinetobacter baumannii.
  • Figure 3 is the bactericidal curve of a compound of another embodiment of the present invention against Staphylococcus aureus 8325-4.
  • the specific detection methods are as follows:
  • Each well contains 50 ⁇ L of ABTGC (10% TSB ABTGC) or contains the compound.
  • MIC minimum inhibitory concentration
  • the minimum inhibitory concentration and minimum bactericidal concentration of compound 1-6 The concentration is not more than 4 ⁇ M, and the minimum inhibitory concentration and minimum bactericidal concentration of the gold compound shown in Comparative Example 1 reach 8 ⁇ M.
  • the minimum inhibitory concentration and minimum bactericidal concentration of compounds 1, 2, 4, and 6 against these four strains of Acinetobacter baumannii were not greater than 2 ⁇ M, showing excellent antibacterial effects. .
  • compound 1 has excellent antibacterial effects on various drug-resistant Acinetobacter baumannii. Compared with the existing common disinfectants, the drug-resistant Acinetobacter baumannii can be effectively killed at a very low concentration. At the same time, there is no significant difference in the antibacterial effect of the compound against different strains of Acinetobacter baumannii.
  • the four strains in Example 1 can be used to reflect the overall antibacterial effect on Acinetobacter baumannii.
  • the highly resistant A. baumannii 53264 and A. baumannii ACICU were selected as the research objects, and the sterilization curve of compound 1 was drawn.
  • the specific experimental steps are as follows:
  • the compound concentration is 0, 1 ⁇ MIC, 2 ⁇ MIC and 4 ⁇ MIC respectively.
  • Each set of experiments contains three technical replicates and three biological replicates.
  • Fig. 1 is a bactericidal curve of a compound of an embodiment of the present invention against the strain A. baumannii 53264 of Acinetobacter baumannii.
  • Fig. 2 is a bactericidal curve of a compound of an embodiment of the present invention against the strain A. baumannii ACICU of Acinetobacter baumannii.
  • the results are shown in Figure 1 and Figure 2.
  • Compound 1 with 2 times the MIC concentration can kill more than 99.9% of A. baumannii 53264 at 40 minutes, and compound 1 with 4 times the MIC concentration can kill more than 99.99 in less than 20 minutes. % Of A. baumannii 53264.
  • Compound 1 with 2 times the MIC concentration can kill more than 99.99% of A.
  • the compound provided in this embodiment can quickly kill drug-resistant Acinetobacter baumannii in a short time, and can be applied to hospitals and other occasions as corresponding antibacterial agents.
  • Example 1 Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Salmonella and Vibrio cholerae were selected and cultured overnight under low-nutrient conditions. Compounds 1-6 in Example 1 were selected as the minimum inhibitory effect on 5 strains. Bacterial concentration (MIC) and minimum bactericidal concentration (MBC) were tested. Refer to Example 1 for the test method, and the test results are shown in Table 3.
  • MIC Bacterial concentration
  • MMC minimum bactericidal concentration
  • the unit of minimum inhibitory concentration and minimum bactericidal concentration is ⁇ M
  • PAO1 is the Pseudomonas aeruginosa in the experiment
  • K.pneumoniae BAA1705 is the strain number of Klebsiella pneumoniae in the experiment
  • E.coli UTI89 is The strain number of Escherichia coli in this experiment
  • S.enteriditis sp. means Salmonella in this experiment
  • V.cholera means Vibrio cholerae in this experiment.
  • the unit of minimum inhibitory concentration and minimum bactericidal concentration is ⁇ M.
  • Example 1 Example 1 for the detection method
  • the detection results are shown in Table 4.
  • the unit of minimum inhibitory concentration and minimum bactericidal concentration is ⁇ M
  • S.aureus 8325-4 and S.aureus101 are the strain numbers of Staphylococcus aureus in the experiment
  • E.faecium 6m6 is the Enterococcus faecium in the experiment The strain number.
  • the unit of minimum inhibitory concentration and minimum bactericidal concentration is ⁇ M.
  • compound 1-6 has excellent antibacterial effects on the three Gram-positive bacteria S.aureus 8325-4, S.aureus101, and E.faecium 6m6. Compared with Comparative Example 1. In comparison, MIC and MBC are significantly lower. Among them, compound 2 has the best antibacterial effect on two strains of Staphylococcus aureus, followed by compound 1, 3, 4 and compound 6. There is little difference in the antibacterial effects of compounds 1-6 on Enterococcus faecium. * Indicates that the strain was cultured with ABTGC containing 10% TSB and subsequent experiments were performed.
  • S. aureus 8325-4 was selected as the Staphylococcus aureus strain to be tested, and the experiment was carried out with reference to Example 3. The result is shown in Fig. 3, which shows that the compound of an embodiment of the present invention is effective against the Staphylococcus aureus strain S. aureus 8325-
  • the bactericidal curve of 4, compound 1 with 4 times the MIC concentration can kill more than 99.99% of S. aureus 8325-4 in about 80 minutes, while the MIC of compound 1 for this strain is only 0.125 ⁇ M.

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Abstract

本发明公开了一类化合物或其药学上可接受的盐在制备抗菌剂中的应用，化合物具有如式（Ⅰ）的结构式。本发明所提供的化合物可以在较低的浓度下快速有效的杀死病菌，从而实现较好的抗菌效果。

Description

金化合物在制备抗菌剂中的应用 技术领域
本发明涉及抗菌剂技术领域，尤其是涉及一类金化合物在制备抗菌剂中的应用。
背景技术
世界卫生组织发布报告称，目前新抗生素的开发严重不足，难以打击日益增长的抗微生物药物耐药性威胁。报告中还确定了12种重点病原体，这些病原体微生物对现有抗生素越来越耐药，迫切需要新的治疗药物。这12种重点病原体中包括了六大耐药菌ESKAPE(肠球菌Enterococcus faecium、金黄色葡萄球菌Staphylococcus aureus、肺炎克雷伯菌Klebsiella pneumoniae、鲍曼不动杆菌Acinetobacter baumannii、铜绿假单胞菌Pseudomonas aeruginosa和肠杆菌属Enterobacter spp.)的一些特定细菌。六大耐药菌广泛分布于自然环境中，属于引发医院感染的重要致病菌，是住院患者特别是重症监护病房免疫力低下患者的常见病原体，可引起医院获得性肺炎、血流感染、中枢神经感染、泌尿系统感染和皮肤软组织感染等，对患者的预后有重大影响。这些菌所具有的强大的获得耐药性和克隆传播的能力引起多重耐药、泛耐药甚至全耐药菌株在世界范围内广泛流行，耐药形势非常严峻，但相应的抗生素的开发则进展缓慢。面对愈发有限的治疗手段，有必要探索其它的抗菌剂。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。为此，本发明提出一类金化合物在制备抗菌剂中的应用。
本发明所采取的技术方案是：
本发明的第一方面，提供一类化合物或其药学上可接受的盐在制备抗菌剂中的应用，化合物具有如下所示的结构式：
Figure PCTCN2019128968-appb-000001
其中，R 1至R 3分别独立选自C1-C6烷基、C1-C6烷氧基和芳基；X 1为卤素。
本发明实施例的有益效果是：
本发明所提供的化合物可以在较低的浓度下快速有效的杀死病菌，从而实现较好的抗菌效果。
根据本发明的一些实施例，R 1至R 3分别独立选自C1-C6烷基、C1-C6烷氧基、苯基。
根据本发明的一些实施例，R 1至R 3分别独立选自C1-C3烷基、C1-C3烷氧基、苯基。
根据本发明的一些实施例，R 1至R 3中苯基的数量不超过一个。
根据本发明的一些实施例，R 1至R 3分别独立选自甲基、乙基、甲氧基、乙氧基。
根据本发明的一些实施例，X 1选自F、Cl、Br、I。
根据本发明的一些实施例，X 1为Cl。
根据本发明的一些实施例，化合物选自：
Figure PCTCN2019128968-appb-000002
根据本发明的一些实施例，化合物选自：
Figure PCTCN2019128968-appb-000003
根据本发明的一些实施例，抗菌剂用于预防和/或治疗细菌的感染，细菌为革兰氏阳性菌或革兰氏阴性菌。
根据本发明的一些实施例，革兰氏阳性菌选自葡萄球菌属和肠球菌属的细菌；革兰氏阴性菌选自不动杆菌属、假单胞菌属、埃希氏菌属、克雷伯菌属、沙门氏菌属、弧菌属的细菌。
根据本发明的一些实施例，革兰氏阳性菌选自金黄色葡萄球菌(Staphylococcus aureus)、屎肠球菌(Enterococcus Faecium)；革兰氏阴性菌选自鲍曼不动杆菌(Acinetobacter baumannii)、铜绿假单胞菌(Pseudomonas aeruginosa)、大肠埃希菌(Escherichia coli)、肺炎克雷伯菌(Klebsiella Pneumoniae)、沙门氏菌(Salmonella enteriditis)、霍乱弧菌(Vibrio cholerae)。
附图说明
图1是本发明的一个实施例的化合物对鲍曼不动杆菌的菌株A.baumannii 53264的杀菌曲线。
图2是本发明的一个实施例的化合物对鲍曼不动杆菌的菌株A.baumannii ACICU的杀菌曲线。
图3是本发明的另一个实施例的化合物对金黄色葡萄球菌S.aureus 8325-4的杀菌曲线。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述，以充分地理解本发明的目的、特征和效果。显然，所描述的实施例只是本发明的一部分实施例，而不是全部实施例，基于本发明的实施例，本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例，均属于本发明保护的范围。
实施例1
Figure PCTCN2019128968-appb-000004
选择4株耐药的鲍曼不动杆菌菌株，在低营养的条件下培养过夜，选择化合物1-6以及对比例1配置后进行对4株鲍曼不动杆菌的最小抑菌浓度(MIC)和最小杀菌浓度(MBC)进行检测。每组实验包含三个技术重复和三个生物重复。(其中，A.baumannii 53264和A.baumannii ACICU为常用的鲍曼不动杆菌耐药菌株，A.baumannii R-1008与A.baumannii 17009来自深圳市第三人民医院)
具体检测方法如下：
①从-80℃冰箱取出冻存的菌液，用接种针蘸取少量菌液按常规方法在LB琼脂板上划线，37℃倒置培养过夜。
②挑取在LB琼脂平板上生长的单个菌落，接种到ABTGC液体培养基中，37℃，200rpm在摇床上过夜培养18h，调节菌液OD值为1，用ABTGC或者含10％TSB的ABTGC液体培养基稀释菌液至细菌的浓度约为1×10 6CFU/mL。
③在96孔板上标记好化合物的浓度，设置好阴性对照，用排枪依此将化合物从最高浓度按照2倍稀释法进行梯度稀释，每孔含有50μL的ABTGC(10％TSB ABTGC)或者含有化合物的ABTGC(10％TSB ABTGC)。
④用排枪依此加入50μL稀释好的菌液，每孔细菌的最终浓度约为5×10 5CFU/mL。将96孔板用保鲜膜封好后，放入37℃恒温培养箱中过夜培养。
⑤观察孔板中细菌生长情况，肉眼看到未长菌的孔对应的化合物的浓度即为最小抑菌浓 度(MIC)。
⑥将MIC、2MIC和4MIC浓度对应的孔板中的液体全部吸出涂在LB琼脂板上，37℃恒温培养箱中倒置培养过夜，第二天观察到LB琼脂板上未长菌的最低化合物浓度即为化合物最小杀菌浓度(MBC)。
结果如表1所示，其中，最小抑菌浓度和最小杀菌浓度的单位为μM，Ab表示鲍曼不动杆菌，其后的数字和字母表示具体的菌株编号。
表1.不同金化合物对鲍曼不动杆菌的MIC和MBC的检测结果
Figure PCTCN2019128968-appb-000005
Figure PCTCN2019128968-appb-000006
从上述结果中可以看到，在A.baumannii ACICU、A.baumannii R-1008、A.baumannii 17009这三株鲍曼不动杆菌的抑制实验中，化合物1-6的最小抑菌浓度和最小杀菌浓度均不大于4μM，而对比例1所示出的金化合物的最小抑菌浓度和最小杀菌浓度则达到8μM。同时，在给出的6种化合物中，化合物1、2、4、6对这四株鲍曼不动杆菌的最小抑菌浓度和最小杀菌浓度均不大于2μM，展现出了较为优异的抗菌效果。
实施例2
Figure PCTCN2019128968-appb-000007
对其中抗菌效果较好的化合物1选择鲍曼不动杆菌的其它耐药菌株进行最小抑菌浓度和最小杀菌浓度的检测，其它各个菌株均同样来源于南方科技大学第二附属医院(深圳市第三人民医院)，检测方法参考实施例1，检测结果如下表所示：
表2.对10株耐药鲍曼不动杆菌的抑菌效果
Figure PCTCN2019128968-appb-000008
从上述结果可以看出，化合物1对于各个耐药的鲍曼不动杆菌均展现出了非常优秀的抑 菌效果。相比现有的普通消毒剂均可以在很低的浓度下有效杀死耐药的鲍曼不动杆菌。同时，化合物对鲍曼不动杆菌的不同菌株的抗菌效果也没有明显差异，可以通过实施例1中的四株菌株反映对鲍曼不动杆菌整体的抗菌效果。
实施例3
Figure PCTCN2019128968-appb-000009
选取高度耐药的A.baumannii 53264和A.baumannii ACICU作为研究对象，绘制化合物1的杀菌曲线，具体实验步骤如下：
①从-80℃冰箱取出冻存的菌液，用接种针蘸取少量菌液按常规方法在LB琼脂板上划线，37℃倒置培养过夜。
②挑取在LB琼脂平板上生长的单个菌落，接种到ABTGC或含有10％TSB的ABTGC液体培养基中，37℃，200rpm在摇床上过夜培养18h，调节菌液OD值为1，用ABTGC或含有10％TSB的ABTGC液体培养基稀释菌液至细菌的浓度约为1×10 6CFU/mL。
③配制化合物浓度分别为0、1×MIC、2×MIC和4×MIC，分别取5mL配置好的化合物于10mL离心管中，加入5mL稀释后菌液，此时每管中所含细菌的量约为5×10 5CFU/mL。将离心管放在37℃，200rpm摇菌。每隔10min检测一次CFU。每组实验包含三个技术重复和三个生物重复。
图1是本发明的一个实施例的化合物对鲍曼不动杆菌的菌株A.baumannii 53264的杀菌曲线。图2是本发明的一个实施例的化合物对鲍曼不动杆菌的菌株A.baumannii ACICU的杀菌曲线。结果如图1和图2所示，2倍MIC浓度的化合物1在第40min即可杀死超过99.9％的A.baumannii 53264，4倍MIC浓度的化合物1在不到20min即可以杀死超过99.99％的A.baumannii 53264。2倍MIC浓度的化合物1在不到40min即可杀死超过99.99％的A.baumannii ACUCU，4倍MIC浓度的化合物1在不到10min即可以杀死超过99.99％的A.baumannii 53264。从上述结果可以看到，本实施例所提供的化合物能够在短时间内快速杀死耐药的鲍曼不动杆菌，从而可以应用到医院等场合作为相应的抗菌剂使用。
实施例4
Figure PCTCN2019128968-appb-000010
选择铜绿假单胞菌、肺炎克雷伯菌、大肠埃希菌、沙门氏菌和霍乱弧菌，在低营养的条件下培养过夜，选择实施例1中的化合物1-6对5种菌株的最小抑菌浓度(MIC)和最小杀 菌浓度(MBC)进行检测，检测方法参考实施例1，检测结果如表3所示。其中，最小抑菌浓度和最小杀菌浓度的单位为μM，PAO1为本实验中的铜绿假单胞菌，K.pneumoniae BAA1705为本实验中的肺炎克雷伯菌的菌株编号，E.coli UTI89为本实验中的大肠埃希菌的菌株编号，S.enteriditis sp.表示本实验中的沙门氏菌，V.cholera表示本实验中的霍乱弧菌。最小抑菌浓度和最小杀菌浓度的单位为μM。
表3.不同金化合物对其它革兰氏阴性菌的MIC和MBC的检测结果
Figure PCTCN2019128968-appb-000011
*表示用含有10％TSB的ABTGC培养菌株并进行后续实验。
实施例5
Figure PCTCN2019128968-appb-000012
选择金黄色葡萄球菌、屎肠球菌，在低营养的条件下培养过夜，选择实施例1中的化合物1-6配置后对2种共3株菌的最小抑菌浓度(MIC)和最小杀菌浓度(MBC)进行检测，检测方法参考实施例1，检测结果如表4所示。其中，最小抑菌浓度和最小杀菌浓度的单位为μM，S.aureus 8325-4、S.aureus101为本实验中的金黄色葡萄球菌的菌株编号，E.faecium 6m6为本实验中的屎肠球菌的菌株编号。最小抑菌浓度和最小杀菌浓度的单位为μM。
表4.不同金化合物对革兰氏阳性菌的MIC和MBC的检测结果
Figure PCTCN2019128968-appb-000013
从上述结果可以看出，化合物1-6对于S.aureus 8325-4、S.aureus101、E.faecium 6m6这三株革兰氏阳性菌均展现出了非常优秀的抑菌效果，与对比例1相比，MIC和MBC明显更低。其中，化合物2对两株金黄色葡萄球菌的抑菌效果最好，其次是化合物1、3、4和化合物6。化合物1-6之间对于屎肠球菌的抑菌效果相差不大。*表示用含有10％TSB的ABTGC培养菌株并进行后续实验。
实施例6
Figure PCTCN2019128968-appb-000014
选择S.aureus 8325-4作为待测的金黄色葡萄球菌，参考实施例3进行实验，结果如图3所示，为本发明的一个实施例的化合物对金黄色葡萄球菌菌株S.aureus 8325-4的杀菌曲线，4倍MIC浓度的化合物1在80min左右即可以杀死超过99.99％的S.aureus 8325-4，而化合物1对该菌株的MIC仅为0.125μM。
实施例7
提供一种如下化合物在制备抗金黄色葡萄球菌的抗菌剂中的应用：
Figure PCTCN2019128968-appb-000015
实施例8
提供一种如下化合物在制备抗鲍曼不动杆菌的抗菌剂中的应用：
Figure PCTCN2019128968-appb-000016
上面结合附图对本发明实施例作了详细说明，但是本发明不限于上述实施例，在所述技术领域普通技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下做出各种变化。

Claims (10)

  1. 化合物或其药学上可接受的盐在制备抗菌剂中的应用，其特征在于，所述化合物具有如下所示的结构式：
    Figure PCTCN2019128968-appb-100001
    其中，R 1至R 3分别独立选自C1-C6烷基、C1-C6烷氧基和芳基；X 1为卤素。
  2. 根据权利要求1所述的应用，其特征在于，R 1至R 3分别独立选自C1-C6烷基、C1-C6烷氧基、苯基。
  3. 根据权利要求2所述的应用，其特征在于，R 1至R 3分别独立选自C1-C3烷基、C1-C3烷氧基、苯基。
  4. 根据权利要求3所述的应用，其特征在于，R 1至R 3分别独立选自甲基、乙基、甲氧基、乙氧基。
  5. 根据权利要求1所述的应用，其特征在于，X 1选自F、Cl、Br、I。
  6. 根据权利要求1所述的应用，其特征在于，所述化合物选自：
    Figure PCTCN2019128968-appb-100002
  7. 根据权利要求6所述的应用，其特征在于，所述化合物选自：
    Figure PCTCN2019128968-appb-100003
  8. 根据权利要求1至7任一项所述的应用，其特征在于，所述抗菌剂用于预防和/或治疗细菌的感染，所述细菌为革兰氏阳性菌或革兰氏阴性菌。
  9. 根据权利要求8所述的应用，其特征在于，所述革兰氏阳性菌选自葡萄球菌属和肠球菌属的细菌；所述革兰氏阴性菌选自不动杆菌属、假单胞菌属、埃希氏菌属、克雷伯菌属、沙门氏菌属、弧菌属的细菌。
  10. 根据权利要求9所述的应用，其特征在于，所述革兰氏阳性菌选自金黄色葡萄球菌、屎肠球菌；所述革兰氏阴性菌选自鲍曼不动杆菌、铜绿假单胞菌、大肠埃希菌、肺炎克雷伯菌、沙门氏菌、霍乱弧菌。
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