鸡毒霉形体不同菌株的药敏实验及耐药机制的研究
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摘要
鸡毒霉形体感染是当前影响禽类生产的常见疾病之一。近年来由于长期使用或滥用抗菌类药物，使得霉形体耐药菌株不断增加，给临床治疗和用药带来困难，同时由于用药增加及药物在禽产品中的残留，也给公共卫生安全带来了隐患。了解鸡毒霉形体国内分离株的耐药情况，探讨耐药性形成机制，对鸡毒霉形体感染的综合性防治及其保障禽类产品的公共卫生安全均具有重要意义。
本研究采用微量稀释法测定了20余株鸡毒霉形体对六种抗生素的最低抑菌浓度，从中筛选出耐药性菌株；用四环素诱导耐药性产生；以PCR法扩增tetM和gyrA基因，并对gyrA基因进行序列测定和比对，探讨了gyrA基因的变异与耐药性生成的关系。结果表明，鸡毒霉形体国内分离株对抗菌药物的敏感性有一定的地区性特点，来自同一地区的分离株对药物的敏感程度较接近，这可能与抗生素使用的频度有关。
gyrA基因测序结果表明，部分菌株的gyrA基因在QRDR区发生碱基突变，部分为沉默突变，没有导致氨基酸发生改变。但是有些碱基突变，导致了与耐药性有关的氨基酸突变，在碱基第249位发生了G→T突变，引起第83位氨基酸由丝氨酸变为异亮氨酸；在碱基第270位发生了T→G突变，引起第90位氨基酸由缬氨酸变为甘氨酸，其他部分菌株也有不同形式的氨基酸突变，结果表明，由于在染色体DNA旋转酶gyrA基因中存在着点突变，造成了大多数霉形体菌株对喹诺酮类药物不同程度的耐药。
Mycoplasma gallisepticum (MG) is a primary pathogen which can induce chronicrespiratory disease (CRD) in chicken. It is a popular disease resulting in great economiclosses, severely influencing poultry industry. Because of frequently using or misusingantibiotic drugs, mycoplasma resistant strains constantly increasing, bring difficulties toclinical cure and medication, and due to the drug residues in livestock products, it also canbring dangers to public health. Therefore, understanding the resistance of MG and studyingits resistance mechanism have great importance to preventing and controlling CRD, andensuring the public health of livestock products.
In this study, susceptibility tests of 20 MG clinical isolates to 6 antibiotics wereperformed by using broth microdilution method, according to the criteria of MIC toselect resistant strains, then used tetracycline to induce resistance. Polymerase chainreaction (PCR) was used to amplify the tetracycline resistance determinant (tetM) andgyrA gene, and gyrA gene was sequenced, then analyzing the sequence with ClustalXsoftware. And the correlation of nucleotide mutations with the resistance to quinoloneswas investigated. Sensitivity testing showed that, sensitivity of MG clinical strains toantibiotics have some area characteristics, and different strains from the same region areclose to each other. It probably associates with the frequent using of antibiotic drugs.
The sequenced result of gyrA indicates that the ORDR of gyrA in some strains havebase mutations, some are silence mutation, not altering the amino acid. But somemutations lead to the change of amino acid, such as a G to T change at site 249 and a Tto G change at site 270, respectively, causing Ser to lie at 83 site and Val to Gly at 90site. The other strains also have different forms of amino acid mutation, inducingresistance of MG to quinolones.
本研究采用微量稀释法测定了20余株鸡毒霉形体对六种抗生素的最低抑菌浓度，从中筛选出耐药性菌株；用四环素诱导耐药性产生；以PCR法扩增tetM和gyrA基因，并对gyrA基因进行序列测定和比对，探讨了gyrA基因的变异与耐药性生成的关系。结果表明，鸡毒霉形体国内分离株对抗菌药物的敏感性有一定的地区性特点，来自同一地区的分离株对药物的敏感程度较接近，这可能与抗生素使用的频度有关。
gyrA基因测序结果表明，部分菌株的gyrA基因在QRDR区发生碱基突变，部分为沉默突变，没有导致氨基酸发生改变。但是有些碱基突变，导致了与耐药性有关的氨基酸突变，在碱基第249位发生了G→T突变，引起第83位氨基酸由丝氨酸变为异亮氨酸；在碱基第270位发生了T→G突变，引起第90位氨基酸由缬氨酸变为甘氨酸，其他部分菌株也有不同形式的氨基酸突变，结果表明，由于在染色体DNA旋转酶gyrA基因中存在着点突变，造成了大多数霉形体菌株对喹诺酮类药物不同程度的耐药。
Mycoplasma gallisepticum (MG) is a primary pathogen which can induce chronicrespiratory disease (CRD) in chicken. It is a popular disease resulting in great economiclosses, severely influencing poultry industry. Because of frequently using or misusingantibiotic drugs, mycoplasma resistant strains constantly increasing, bring difficulties toclinical cure and medication, and due to the drug residues in livestock products, it also canbring dangers to public health. Therefore, understanding the resistance of MG and studyingits resistance mechanism have great importance to preventing and controlling CRD, andensuring the public health of livestock products.
In this study, susceptibility tests of 20 MG clinical isolates to 6 antibiotics wereperformed by using broth microdilution method, according to the criteria of MIC toselect resistant strains, then used tetracycline to induce resistance. Polymerase chainreaction (PCR) was used to amplify the tetracycline resistance determinant (tetM) andgyrA gene, and gyrA gene was sequenced, then analyzing the sequence with ClustalXsoftware. And the correlation of nucleotide mutations with the resistance to quinoloneswas investigated. Sensitivity testing showed that, sensitivity of MG clinical strains toantibiotics have some area characteristics, and different strains from the same region areclose to each other. It probably associates with the frequent using of antibiotic drugs.
The sequenced result of gyrA indicates that the ORDR of gyrA in some strains havebase mutations, some are silence mutation, not altering the amino acid. But somemutations lead to the change of amino acid, such as a G to T change at site 249 and a Tto G change at site 270, respectively, causing Ser to lie at 83 site and Val to Gly at 90site. The other strains also have different forms of amino acid mutation, inducingresistance of MG to quinolones.
引文
1．艾武，牟建青，刘玉山等．鸡毒支原体敏感药物的筛选．中国兽药杂志，2003，37(5)：48-49
2．毕丁仁．霉形体病鸡群带菌持续时间．中国兽医杂志，1986，(3)：30
3．陈代杰．抗菌药物与细菌耐药性．上海：华东理工大学出版社，2001：120-129
4．邓显文，谢芝勋，刘加波．广西鸡毒霉形体血清学调查．广西畜牧兽医，1990，13(1)：22-24
5．傅先强．控制鸡霉形体病的新思路．中国家禽，2000，22(8)：5-6
6．郭锐．鸡毒霉形体的分离鉴定及其16S／23S rRNA基因间隔区、TM-1基因序列差异分析．[硕士学位论文]．武汉：华中农业大学图书馆，2006
7．韩文瑜，冯书章．现代分子病原细菌学．吉林人民出版社，2003：137-148
8．冀锡霖，宁宜宝．鸡感染鸡毒霉形体和滑液霉形体情况的调查．中国兽医科技，1986，(4)：16-18
9．蒋红霞．耐FQs鸡毒支原体gyrA基因突变研究及检测芯片的研制．[博士学位论文]．广州：华南农业大学图书馆，2002
10．雷连成．细菌的耐药性．中国兽药杂志，2002，36(11)：1225-1500
11．糜祖煌，赵季文．重视支原体研究提高支原体检测水平．中华检验医学杂志，2005，28：677-678
12．宁宜宝．动物支原体病预防与控制的研究进展．中国兽药杂志，1999，33(1)：45-48
13．牛建强，王正党，叶志远，王永辉，刘晓明．鸡源霉形体的分离和鉴定．中国兽医科技，2002，32(2)：23-24
14．吴惠明．耐大环内酯类药物鸡毒支原体的诱导和耐药基因的突变分析．[硕士学位论文]．北京：中国农业大学图书馆，2004
15．谢轶，杨维青，贾文祥等．铜绿假单胞菌耐药性在生物被膜形成过程中的变化．中华微生物学和免疫学杂志，2005，25(4)：314-318
16．张冉，吴移谋，向斌等．次抑菌浓度的喹诺酮类药物诱导人型支原体耐药耐药与交叉耐药的研究．实用预防兽医学，2000，7(1)：12-14
17．朱翠明，吴移谋，余敏君等．次抑菌浓度的药物诱导解脲支原体、人型支原体耐药与交叉耐药的研究．中国皮肤性病学杂志，2000，14(2)：86-87
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19. Archer G L, Climo M W. Antimicrobial susceptibility of coagulase-negative staphylococci. Antimicrob Agents Chemother, 1994,38(10): 2231-2237
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21. Gautier A V, Reinhardt A K, Kobisch M, Kempf I. In vitro development of resistance to enrofloxacin, erythromycin, tylosin, tiamulin and oxytetracycline in Mycoplasma gallisepticum, Mycoplasma iowae and Mycoplasma synoviae, Veterinary Microbiology, 2002:47-58
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24. Boos M, Mayer S, Fischer A. In vitro development of resistance to six quinolones in Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. Antimicrob Agents and Chemother, 2001,45 (3): 938-942
25. Burns J L, Wadsworth C D, Barry J J, and Goodall C P. Nucleotide sequence analysis of a gene from Burkholderia (Pseudomonas) cepacia encoding an outer membrane lipoprotein involved in multiple antibiotic resistance. Antimicrob Agents Chemother, 1996,40(2): 307- 313
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2．毕丁仁．霉形体病鸡群带菌持续时间．中国兽医杂志，1986，(3)：30
3．陈代杰．抗菌药物与细菌耐药性．上海：华东理工大学出版社，2001：120-129
4．邓显文，谢芝勋，刘加波．广西鸡毒霉形体血清学调查．广西畜牧兽医，1990，13(1)：22-24
5．傅先强．控制鸡霉形体病的新思路．中国家禽，2000，22(8)：5-6
6．郭锐．鸡毒霉形体的分离鉴定及其16S／23S rRNA基因间隔区、TM-1基因序列差异分析．[硕士学位论文]．武汉：华中农业大学图书馆，2006
7．韩文瑜，冯书章．现代分子病原细菌学．吉林人民出版社，2003：137-148
8．冀锡霖，宁宜宝．鸡感染鸡毒霉形体和滑液霉形体情况的调查．中国兽医科技，1986，(4)：16-18
9．蒋红霞．耐FQs鸡毒支原体gyrA基因突变研究及检测芯片的研制．[博士学位论文]．广州：华南农业大学图书馆，2002
10．雷连成．细菌的耐药性．中国兽药杂志，2002，36(11)：1225-1500
11．糜祖煌，赵季文．重视支原体研究提高支原体检测水平．中华检验医学杂志，2005，28：677-678
12．宁宜宝．动物支原体病预防与控制的研究进展．中国兽药杂志，1999，33(1)：45-48
13．牛建强，王正党，叶志远，王永辉，刘晓明．鸡源霉形体的分离和鉴定．中国兽医科技，2002，32(2)：23-24
14．吴惠明．耐大环内酯类药物鸡毒支原体的诱导和耐药基因的突变分析．[硕士学位论文]．北京：中国农业大学图书馆，2004
15．谢轶，杨维青，贾文祥等．铜绿假单胞菌耐药性在生物被膜形成过程中的变化．中华微生物学和免疫学杂志，2005，25(4)：314-318
16．张冉，吴移谋，向斌等．次抑菌浓度的喹诺酮类药物诱导人型支原体耐药耐药与交叉耐药的研究．实用预防兽医学，2000，7(1)：12-14
17．朱翠明，吴移谋，余敏君等．次抑菌浓度的药物诱导解脲支原体、人型支原体耐药与交叉耐药的研究．中国皮肤性病学杂志，2000，14(2)：86-87
18. Aarestrup F M, Seyfarth A M, Emborg H D. Effect of abolishment of the use of antimicrobial agents for growth promotion on occurrence of antimicrobial resistance in fecal enterococci from food animals in denmark. Antimicrob Agents Chemother, 2001, 45(7): 2054
19. Archer G L, Climo M W. Antimicrobial susceptibility of coagulase-negative staphylococci. Antimicrob Agents Chemother, 1994,38(10): 2231-2237
20. Austin D J, Knstinsson K G, Anderson R M. The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. ProcNatl Acad Sci USA, 1999, 96(3): 1152
21. Gautier A V, Reinhardt A K, Kobisch M, Kempf I. In vitro development of resistance to enrofloxacin, erythromycin, tylosin, tiamulin and oxytetracycline in Mycoplasma gallisepticum, Mycoplasma iowae and Mycoplasma synoviae, Veterinary Microbiology, 2002:47-58
22. Baseggio N, Glew M D, Markham P F, Whithear K G, Browning G F. Size and genomic location of the pMGA multigene family of Mycoplasma galliseptium. Microbiology, 1996,142:1429-1435
23. Blanchard A, Crabb D W, Dybvig K. Rapid detection of tetM in Mycoplasma hominis and Ureaplasma urealyticum by PCR: tetM confers resistance to tetracycline but not necessaily to doxycycline. FEMS Microbiol Lett, 1992, 95: 277-282
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