黄芩素与β-内酰胺类抗生素对耐甲氧西林金黄色葡萄球菌的协同抗菌作用研究
摘要
一、MRSA(耐甲氧西林金黄色葡萄球菌)耐药表型和SCCmec基因分型
目的
了解汕头大学医学院附属第一医院分离的92株MRSA的耐药情况及其SCCmec基因型。
方法
1.提取细菌的基因组DNA,用聚合酶链反应(PCR)扩增MRSA携带的mecA基因,鉴定MRSA菌株
2.琼脂稀释法测定16种抗菌药物对MRSA的最低抑菌浓度(MIC)。
3.多重PCR扩增检测MRSA的SCCmec分子分型。
结果
1.92株MRSA均携带mecA基因。
2. 92株MRSA对实验中所有β-内酰胺类抗生素的耐药率均在80%以上。绝大部分菌株对庆大霉素、红霉素、氟喹诺酮类也不敏感。超过半数的MRSA菌株对利福平保持敏感,对氯霉素,多西环素及米诺环素也普遍敏感,未发现耐万古霉素的MRSA菌株。
3.临床分离株中以SCCmec III和IIIA型为主,该结果与亚洲多数国家分离的MRSA的SCCmec分型一致。
结论
1.我院第一附属医院的MRSA呈多重耐药,但对氯霉素,半合成四环素及万古霉素仍然敏感。
2.临床分离株中以SCCmec III和IIIA型为主,说明HA-MRSA为该院的主要流行菌株。
二、黄芩素与β-内酰胺类抗生素对MRSA的协同抗菌作用机制研究
目的
探讨黄芩素与β-内酰胺类抗生素合用对MRSA的协同抗菌作用机制。
方法
1.以微量稀释法测定单用黄芩素的最低抑菌浓度(MIC),并以微量棋盘稀释法测定黄芩素与β-内酰胺类抗生素的协同抗菌作用。
2.应用AFFX原核表达谱芯片测定黄芩素对MRSA全基因组表达影响,Real-time PCR验证基因芯片结果。
3.蛋白印迹法(Western-blot)检测黄芩素对PBP2a的表达的影响,采用荧光凝胶成像技术检测黄芩素对青霉素结合蛋白的作用。
4.高效液相色谱法检测黄芩素对头孢唑啉在MRSA菌体内摄取浓度的影响。
5.提取自溶酶粗提液和细胞壁粗提物,用SDS-PAGE凝胶电泳检测黄芩素对MRSA自溶酶谱及活性的影响。
6.酶标仪检测黄芩素对β-内酰胺酶活性的抑制作用。
结果
1.单用黄芩素的MIC值在64-128μg/ml之间, 32μg/ml的黄芩素能使MRSA及ATCC 25923对苯唑西林,头孢唑啉及氨苄西林的敏感性增高,FIC(The fractional inhibitory concentration)指数在0.266到0.75之间,结果显示,32μg/ml黄芩素与苯唑西林,头孢唑啉与氨苄西林合用对MRSA有协同抗菌作用。
2.基因芯片实验结果显示,黄芩素使164个基因表达上调,其中功能明确的基因有53个,332个基因表达下调,功能明确的基因有64个。这些基因主要包括基础代谢有关基因,转运子基因,转录调控有关的基因,DNA复制及修复,细菌自溶酶以及甲基化酶基因等。经Real-time PCR验证,结果与基因芯片结果相符。
3. Western-blot结果显示:黄芩素单用或与苯唑西林合用并未能使MRSA所产的PBP2a表达显著下降。荧光凝胶成像结果显示:黄芩素不能诱导PBPs的表达增加,也未能显著影响各PBPs蛋白与Bocillin-FL的亲和力。
4.黄芩素能使头孢唑啉在MRSA的菌体内的蓄积浓度显著增加。
5.黄芩素能使MRSA的自溶酶表达增加,或能使自溶酶水解细胞壁的活性增强。
6.黄芩素对MRSA所产的β-内酰胺酶的活性没有显著抑制作用。
结论
黄芩素与β-内酰胺类抗生素对MRSA有协同抗菌作用,能显著降低β-内酰胺类抗生素的最低抑菌浓度。黄芩素逆转MRSA的作用机制可能与以下几个方面有关:
1.黄芩素能抑制耐药泵的表达,这一作用可使β-内酰胺类抗生素在菌体的摄取浓度增高,增加MRSA对抗生素的敏感性的作用;
2.黄芩素干扰了DNA的复制和修复,增加了抗生素对MRSA的毒性作用;
3.黄芩素通过影响某些甲基化酶及核糖体蛋白的表达,阻碍了正常的蛋白质合成过程;
4.黄芩素能诱导MRSA的自溶酶系统,使MRSA对抗生素的敏感性增加。
Antimicrobial resistance phenotypes and SCCmec genotypes of Methicillin-resistant Staphylococcus aureus (MRSA) isolates
Objective
To investigate the antimicrobial resistance phenotypes and SCCmec genotypes of 92 MRSA isolates in the first affiliated hospital, Shantou university medical college. Methods
1.The bacterial genomic DNA was extracted and polymerase chain reaction (PCR) was used to detect of the mecA gene of MRSA strains.
2. The minimum inhibitory concentrations (MICs) of 16 antimicrobial agents against MRSA were testeded by agar dilution method.
3. SCCmec types of MRSA isolates were determined by multiplex PCR. Results
1. MecA gene was detected in all of 92 MRSA strains.
2. More than 80% of MRSA strains were resistant to all of the testedβlactam antibiotics. Most of the strains were resistant to gentamycin, erythromycin and fluoroquinolones while more than half of MRSA strains were susceptible to rifampicin. Chloramphenicol, doxycycline and minocycline still remained a high activity against MRSA isolates. Vancomycin resistant Staphylcoccus aureus was not found in this study.
3. SCCmecIII and IIIA were predominant types among the cilinal MRSA isolates. This result was consistent with previous reports that SCCmec III and IIIA types were predominant in most Asian countries.
Conclusions
1. Antimicrobial resistance of MRSA isolates in the first affiliated hospital, Shantou University Medical college are multidrug resistant. However, chloramphenicol, semi-synthetic tetracyclines and vancomycin are highly effective against MRSA isolates.
2. SCCmecIII and IIIA were predominant types among the MRSA isolates suggesting that most of the MRSA isolates in this study may have originated from HA-MRSA.
Mechanism of synergic effect between baicalein andβlactams against MRSA
Objective
To investigate the mechanisms of synergic effects of baicalein in combination withβlatams against MRSA. Methods
1. The minimum inhibitory concentrations (MICs) of baicalein alone and in combination withβlactams against MRSA isolates were determined by agar dilution method and microdilution checkboard method.
2. Global transcriptional response of Staphylococcus aureus to baicalein was analysed by AFFX GeneChips and confirmed by real time PCR.
3. Western blot was performed to dectect the expression of PBP2a produced by MRSA isolates affected by baicalein. Fluroimage was used to analyse the production and binding ability of PBPs of MRSA after treated with baicalein.
4. Crude autolysis enzyme and cell wall were extracted. MRSA autolysis profile and activity were analysed by SDS-PAGE electrophoresis.
5. Activity ofβ-lactamase inhibited by baicalein was detected by microplate reader.
6. The activity ofβ-lactamase was not significantly inhibited by baicalein.
Reusults
1. The MICs of baicalein alone against MRSA isolates ranged from 64 to 128μg/ml. 32μg/ml baicalein remarkablely reduced the MICs of cefazolin, oxacillin and ampicillin against MRSA and ATCC25923 with FIC index range from 0.266 to 0.75. These results revealed the synergism of cefazolin, oxacillin and ampicillin against MRSA in combination with 32μg/ml baicalein.
2. The results of GeneChips showed that 164 genes were remarkably upregulated by baicalein, 53 of which were identified genes. 332 genes were downregulated, 64 of which were identified genes. The functions of these differentially expressed genes were involved in basic metabolism, gene transcription regulation, transporter, DNA repair and replication,autolysin and methylation. The results of real– time PCR were in consistent with those of Genechips.
3. The results of Western blot revealed that PBP2a expression of MRSA did not decrease significantly when treated with baicalein. Fluorescence image resulte showed that the baicalein did not either induce the production of PBPs or interfere with the affinity between PBPs and Bocillin - FL .
4. Baicalein increased the uptake of cafazolin into MRSA.
5. Baicalein increased the expression of autolytic system or induced the activity of autolysin.
Conclusion
There is a synergic effect between baicalein andβlactam antibiotics against MRSA. Baicalein significantly decreases the MICs ofβlactam antibiotics against MRSA isolates. The following factors may involve in the mechanisms of the restoration of susceptibily of MRSA toβlactams by baicalein.
1. Bacalein may inhibit expression of multidrug-resistant transporter, which increases the concentration of the antibiotic uptake and enhances the susceptibility ofβlactams of MRSA.
2. Baicalein probably interferes with the process of DNA replication and repair, and therefore increases the toxic effects of antibiotics against MRSA.
3. The expression of some methylase and ribosomal protein may be inhibited by baicalein so that hinder the normal process of protein synthesis.
4. Baicalein triggers the autolysis system of MRSA, which may also involve in the mechasnims of enhanced antibacterial effects ofβlactam antibiotics.
目的
了解汕头大学医学院附属第一医院分离的92株MRSA的耐药情况及其SCCmec基因型。
方法
1.提取细菌的基因组DNA,用聚合酶链反应(PCR)扩增MRSA携带的mecA基因,鉴定MRSA菌株
2.琼脂稀释法测定16种抗菌药物对MRSA的最低抑菌浓度(MIC)。
3.多重PCR扩增检测MRSA的SCCmec分子分型。
结果
1.92株MRSA均携带mecA基因。
2. 92株MRSA对实验中所有β-内酰胺类抗生素的耐药率均在80%以上。绝大部分菌株对庆大霉素、红霉素、氟喹诺酮类也不敏感。超过半数的MRSA菌株对利福平保持敏感,对氯霉素,多西环素及米诺环素也普遍敏感,未发现耐万古霉素的MRSA菌株。
3.临床分离株中以SCCmec III和IIIA型为主,该结果与亚洲多数国家分离的MRSA的SCCmec分型一致。
结论
1.我院第一附属医院的MRSA呈多重耐药,但对氯霉素,半合成四环素及万古霉素仍然敏感。
2.临床分离株中以SCCmec III和IIIA型为主,说明HA-MRSA为该院的主要流行菌株。
二、黄芩素与β-内酰胺类抗生素对MRSA的协同抗菌作用机制研究
目的
探讨黄芩素与β-内酰胺类抗生素合用对MRSA的协同抗菌作用机制。
方法
1.以微量稀释法测定单用黄芩素的最低抑菌浓度(MIC),并以微量棋盘稀释法测定黄芩素与β-内酰胺类抗生素的协同抗菌作用。
2.应用AFFX原核表达谱芯片测定黄芩素对MRSA全基因组表达影响,Real-time PCR验证基因芯片结果。
3.蛋白印迹法(Western-blot)检测黄芩素对PBP2a的表达的影响,采用荧光凝胶成像技术检测黄芩素对青霉素结合蛋白的作用。
4.高效液相色谱法检测黄芩素对头孢唑啉在MRSA菌体内摄取浓度的影响。
5.提取自溶酶粗提液和细胞壁粗提物,用SDS-PAGE凝胶电泳检测黄芩素对MRSA自溶酶谱及活性的影响。
6.酶标仪检测黄芩素对β-内酰胺酶活性的抑制作用。
结果
1.单用黄芩素的MIC值在64-128μg/ml之间, 32μg/ml的黄芩素能使MRSA及ATCC 25923对苯唑西林,头孢唑啉及氨苄西林的敏感性增高,FIC(The fractional inhibitory concentration)指数在0.266到0.75之间,结果显示,32μg/ml黄芩素与苯唑西林,头孢唑啉与氨苄西林合用对MRSA有协同抗菌作用。
2.基因芯片实验结果显示,黄芩素使164个基因表达上调,其中功能明确的基因有53个,332个基因表达下调,功能明确的基因有64个。这些基因主要包括基础代谢有关基因,转运子基因,转录调控有关的基因,DNA复制及修复,细菌自溶酶以及甲基化酶基因等。经Real-time PCR验证,结果与基因芯片结果相符。
3. Western-blot结果显示:黄芩素单用或与苯唑西林合用并未能使MRSA所产的PBP2a表达显著下降。荧光凝胶成像结果显示:黄芩素不能诱导PBPs的表达增加,也未能显著影响各PBPs蛋白与Bocillin-FL的亲和力。
4.黄芩素能使头孢唑啉在MRSA的菌体内的蓄积浓度显著增加。
5.黄芩素能使MRSA的自溶酶表达增加,或能使自溶酶水解细胞壁的活性增强。
6.黄芩素对MRSA所产的β-内酰胺酶的活性没有显著抑制作用。
结论
黄芩素与β-内酰胺类抗生素对MRSA有协同抗菌作用,能显著降低β-内酰胺类抗生素的最低抑菌浓度。黄芩素逆转MRSA的作用机制可能与以下几个方面有关:
1.黄芩素能抑制耐药泵的表达,这一作用可使β-内酰胺类抗生素在菌体的摄取浓度增高,增加MRSA对抗生素的敏感性的作用;
2.黄芩素干扰了DNA的复制和修复,增加了抗生素对MRSA的毒性作用;
3.黄芩素通过影响某些甲基化酶及核糖体蛋白的表达,阻碍了正常的蛋白质合成过程;
4.黄芩素能诱导MRSA的自溶酶系统,使MRSA对抗生素的敏感性增加。
Antimicrobial resistance phenotypes and SCCmec genotypes of Methicillin-resistant Staphylococcus aureus (MRSA) isolates
Objective
To investigate the antimicrobial resistance phenotypes and SCCmec genotypes of 92 MRSA isolates in the first affiliated hospital, Shantou university medical college. Methods
1.The bacterial genomic DNA was extracted and polymerase chain reaction (PCR) was used to detect of the mecA gene of MRSA strains.
2. The minimum inhibitory concentrations (MICs) of 16 antimicrobial agents against MRSA were testeded by agar dilution method.
3. SCCmec types of MRSA isolates were determined by multiplex PCR. Results
1. MecA gene was detected in all of 92 MRSA strains.
2. More than 80% of MRSA strains were resistant to all of the testedβlactam antibiotics. Most of the strains were resistant to gentamycin, erythromycin and fluoroquinolones while more than half of MRSA strains were susceptible to rifampicin. Chloramphenicol, doxycycline and minocycline still remained a high activity against MRSA isolates. Vancomycin resistant Staphylcoccus aureus was not found in this study.
3. SCCmecIII and IIIA were predominant types among the cilinal MRSA isolates. This result was consistent with previous reports that SCCmec III and IIIA types were predominant in most Asian countries.
Conclusions
1. Antimicrobial resistance of MRSA isolates in the first affiliated hospital, Shantou University Medical college are multidrug resistant. However, chloramphenicol, semi-synthetic tetracyclines and vancomycin are highly effective against MRSA isolates.
2. SCCmecIII and IIIA were predominant types among the MRSA isolates suggesting that most of the MRSA isolates in this study may have originated from HA-MRSA.
Mechanism of synergic effect between baicalein andβlactams against MRSA
Objective
To investigate the mechanisms of synergic effects of baicalein in combination withβlatams against MRSA. Methods
1. The minimum inhibitory concentrations (MICs) of baicalein alone and in combination withβlactams against MRSA isolates were determined by agar dilution method and microdilution checkboard method.
2. Global transcriptional response of Staphylococcus aureus to baicalein was analysed by AFFX GeneChips and confirmed by real time PCR.
3. Western blot was performed to dectect the expression of PBP2a produced by MRSA isolates affected by baicalein. Fluroimage was used to analyse the production and binding ability of PBPs of MRSA after treated with baicalein.
4. Crude autolysis enzyme and cell wall were extracted. MRSA autolysis profile and activity were analysed by SDS-PAGE electrophoresis.
5. Activity ofβ-lactamase inhibited by baicalein was detected by microplate reader.
6. The activity ofβ-lactamase was not significantly inhibited by baicalein.
Reusults
1. The MICs of baicalein alone against MRSA isolates ranged from 64 to 128μg/ml. 32μg/ml baicalein remarkablely reduced the MICs of cefazolin, oxacillin and ampicillin against MRSA and ATCC25923 with FIC index range from 0.266 to 0.75. These results revealed the synergism of cefazolin, oxacillin and ampicillin against MRSA in combination with 32μg/ml baicalein.
2. The results of GeneChips showed that 164 genes were remarkably upregulated by baicalein, 53 of which were identified genes. 332 genes were downregulated, 64 of which were identified genes. The functions of these differentially expressed genes were involved in basic metabolism, gene transcription regulation, transporter, DNA repair and replication,autolysin and methylation. The results of real– time PCR were in consistent with those of Genechips.
3. The results of Western blot revealed that PBP2a expression of MRSA did not decrease significantly when treated with baicalein. Fluorescence image resulte showed that the baicalein did not either induce the production of PBPs or interfere with the affinity between PBPs and Bocillin - FL .
4. Baicalein increased the uptake of cafazolin into MRSA.
5. Baicalein increased the expression of autolytic system or induced the activity of autolysin.
Conclusion
There is a synergic effect between baicalein andβlactam antibiotics against MRSA. Baicalein significantly decreases the MICs ofβlactam antibiotics against MRSA isolates. The following factors may involve in the mechanisms of the restoration of susceptibily of MRSA toβlactams by baicalein.
1. Bacalein may inhibit expression of multidrug-resistant transporter, which increases the concentration of the antibiotic uptake and enhances the susceptibility ofβlactams of MRSA.
2. Baicalein probably interferes with the process of DNA replication and repair, and therefore increases the toxic effects of antibiotics against MRSA.
3. The expression of some methylase and ribosomal protein may be inhibited by baicalein so that hinder the normal process of protein synthesis.
4. Baicalein triggers the autolysis system of MRSA, which may also involve in the mechasnims of enhanced antibacterial effects ofβlactam antibiotics.
引文
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[29]Cha HY, Moon DC, Choi CH,et al. Prevalence of the ST239 clone of methicillin-resistant Staphylococcus aureus and differences in antimicrobial susceptibilities of ST239 and ST5 clones identifiedin a Korean hospital. J Clin. Microbiol. 2005,43: 3610-3614.
[30] Cunha BA. New uses for older antibiotics: nitrofurantoin, amikacin, colistin, polymyxin B, doxycycline, and minocycline revisited. Med. Clin. North. Am. 2006, 90: 1089-1107.
[31] Kim HB, Jang HC, Nam HJ, et al. In vitro activities of 28 antimicrobial agents against Staphylococcus aureus isolates from tertiary-care hospitals in Korea: a nationwide survey. Antimicrob. Agents Chemother. 2004, 48:1124-1127.
[32] Ko KS, Lee JY, Suh JY,et al. Distribution of major genotypes among methicillin-resistant Staphylococcus aureus clones in Asian countries. J. Clin. Microbiol. 2005,43: 421-426.
[33] Fatholahzadeh B, Emaneini M, Gilbert G., et al. Staphylococcal cassette chromosome mec (SCCmec) analysis and antimicrobial susceptibility patterns of methicillin-resistant Staphylococcus aureus (MRSA) isolates in Tehran, Iran. Microb. Drug. Resist. 2008,14: 217-220.
[34] Kilic A, Guclu AU, Senses Z, Bedir O, Aydogan H, Basustaoglu AC. Staphylococcal cassette chromosome mec (SCCmec) characterization and panton-valentine leukocidin gene occurrence for methicillin-resistant Staphylococcus aureus in Turkey, from 2003 to 2006. Antonie. Van. Leeuwenhoek. 2008, 94: 607-614.
[35] Faria NA, Carrico JA,Oliveira DC.Analysis of typing methods forepidemiological surveillance of both methicillin-resistant and methicillin-susceptible Staphylococcus aureus strains. J Clin Microbiol.2008,46(1):136-144
[1] Lee JW, Ji YJ, Lee SO, et al. Effect of Saliva miltiorrhiza bunge on antimicrobial activity and resistant gene regulation against methicillin-resistant Staphylococcus aureus (MRSA). J Microbiol, 2007, 45(4): 350-7.
[2] Yu HH, Kim KJ, Cha JD, et al. Antimicrobial activity of berberinealone and in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. J Med Food, 2005,8(4): 454-461.
[3] Fujita M, Shiota S, Kuroda T, et al. Remarkable synergies between baicalein and tetracycline, and baicalein and beta-lactams against methicillin-resistant Staphylococcus aureus. Microbiol Immunol, 2005, 49(4): 391-396.
[4] Yu L, Xiang H, Fan J, et al. Global transcriptional response of Staphylococcus aureus to rhein, a natural plant product. J Biotechnol, 2008,135(3): 304-308.
[5] Feng H, Xiang H, Zhang J, et al. Genome-wide transcriptional profiling of the response of Staphylococcus aureus to cryptotanshinone. J Biomed Biotechnol, 2009,2009: 617509.
[6] Stapleton PD, Shah S, Ehlert K, et al. Theβ-lactam-resistance modifier (-)-epicatechin gallate alters the architecture of the cell wall of Staphylococcus aureus. Microbiology, 2007,153(7): 2093-2103.
[7] Sieradzki, K. and A. Tomasz, Inhibition of the autolytic system by vancomycin causes mimicry of vancomycin-intermediate Staphylococcus aureus-type resistance, cell concentration dependence of the MIC, and antibiotic tolerance in vancomycin-susceptible S. aureus. Antimicrob Agents Chemother,2006,50(2): 527-533.
[8] Sieradzki, K. and A. Tomasz, Inhibition of cell wall turnover and autolysis by vancomycin in a highly vancomycin-resistant mutant of Staphylococcus aureus. J Bacteriol, 1997,179(8): 2557-2566.
[9] Sieradzki K, Tomasz A. Inhibition of the autolytic system by vancomycin causes mimicry of vancomycin-intermediate Staphylococcus aureus-type resistance,cell concentration dependence of the MIC,and antibiotic tolerance in vancomycin- susceptible S.aureus. Antimicrob Agents Chemother, 2006,50(2): 527-533.
[10] Chambers HF. Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications. Clin Microbiol Rev, 1997,10(4): 781-91.
[11] Parvez MA, Shibata H, Nakano T, et al. No relationship exists between PBP 2a amounts expressed in different MRSA strains obtained clinically and their beta-lactam MIC values. J Med Invest, 2008, 55(3-4): 246-253.
[12] Pereira SF, Henriques AO, Pinho MG, et al. Role of PBP1 in cell division of Staphylococcus aureus. J Bacteriol, 2007,189(9): 3525-3531.
[13] Pereira SF, Henriques AO, Pinho MG, et al. Evidence for a dual role of PBP1 in the cell division and cell separation of Staphylococcusaureus. Mol Microbiol, 2009,72(4): 895-904.
[14] Henze UU and Berger-Bachi B. Penicillin-binding protein 4 overproduction increases beta-lactam resistance in Staphylococcus aureus. Antimicrob Agents Chemother, 1996,40(9): 2121-2125.
[15] Stapleton PD. and Taylor PW. Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. Sci Prog, 2002,85(Pt 1): 57-72.
[16] Putman M, van Veen HW, Konings WN. Molecular properties of bacterial multidrug transporters. Microbiol Mol Biol Rev, 2000 , 64(4): 672-93.
[17] Davidson, A.L., et al., Structure, function, and evolution of bacterial ATP-binding cassette systems. Microbiol Mol Biol Rev, 2008,72(2): 317-364.
[18] Braun V. Bacterial iron transport related to virulence. Contrib Microbiol, 2005,12: 210-33.
[19] Davidson AL, Dassa E, Orelle C, et al. DNA helicase activity of PcrA is not required for the displacement of RecA protein from DNA or inhibition of RecA-mediated strand exchange. J Bacteriol, 2007,189(12): 4502-4509.
[20] Chang TL, Naqvi A, Anand SP, et al. Biochemical characterization of the Staphylococcus aureus PcrA helicase and its role in plasmid rolling circle replication. J Biol Chem, 2002,277(48): 45880-6.
[21] Lusetti SL, Cox MM. The bacterial RecA protein and the recombinational DNA repair of stalled replication forks. Annu Rev Biochem, 2002,71: 71-100.
[22] Rodnina MV, Beringer M, Wintermeyer W. How ribosomes make peptide bonds. Trends Biochem Sci, 2007,32(1): 20-26.
[23] Antignac A, Sieradzki K, Tomasz A. Perturbation of cell wall synthesis suppresses autolysis in Staphylococcus aureus: evidence for coregulation of cell wall synthetic and hydrolytic enzymes. J Bacteriol, 2007,189(21): 7573-7580.
[24] Tomasz A, Waks S. Mechanism of action of penicillin: triggering of the pneumococcal autolytic enzyme by inhibitors of cell wall synthesis. Proc Natl Acad Sci, 1975,72(10): 4162-4166.
[25] Biziulevicius, G.A., G. Biziuleviciene, and J. Kazlauskaite, Lysozyme and similar lytic enzyme preparations should be considered antibiotics. Med Hypotheses, 2007,68(6): 1420.
[26] Biziulevicius GA, Biziuleviciene G, Kazlauskaite J. Characterization of sodium dodecyl sulfate-stable Staphylococcus aureus bacteriolytic enzymes by polyacrylamide gel electrophoresis. J Bacteriol, 1990,172(11): 6494-6498.
[27]王军华,权春善,郑维等.金黄色葡萄球菌附属基因调节系统.中国生物工程杂志. 2008, 28(6): 93-99.
[28] Sugai M, Akiyama T, Komatsuzawa H, et al. Regulation of riboflavinbiosynthesis and transport genes in bacteria by transcriptional and translational attenuation. Nucleic Acids Res, 2002 , 30(14): 3141-3151.
[29] Vitreschak AG, Rodionov DA, Mironov AA, et al. Riboflavin biosynthetic and regulatory factors as potential novel anti-infective drug targets. Chem Biol Drug Des, 2010,75(4): 339-347.
[30] Zhao G, Meier TI, Kahl SD, et al. BOCILLIN FL, a sensitive and commercially available reagent for detection of penicillin-binding proteins. Antimicrob Agents Chemother, 1999, 43(5): 1124-1128
[31] Nikaido H .Preventing drug access to targets: cell surface permeability barriers and active efflux in bacteria. Semin Cell Dev Biol, 2001, 12(3): 215-223
[1] Jevons MP." Celbenin" -resistant staphylococci. Br Med J.1961, 1(2) :124-125
[2] Enright MC. Genome of an epidemic community-acquired MRSA. Lancet. 2006,367(9512): 705-706.
[3] Klein E, Smith DL, Laxminarayan R. Hospitalizations and Deaths Caused by Methicillin-Resistant Staphylococcus aureus, United States, 1999–2005. Emerg Infect Dis .2007,13 (12): 1840–1846.
[4]梁锦湄,梁蓓蓓,王睿.耐甲氧西林金葡球菌的研究进展.中国新药杂志,2008,17(13):1097-1100
[5]李红玉,李国成,潘昆贻等. 2000-2003年广州地区耐甲氧西林金黄色葡萄球菌耐药变迁及治疗对策.广东药学,2006,6(15): 31-33
[6]李家泰,齐慧敏,李耘. 2002-2003年中国医院和社区获得性感染革兰阳性细菌耐药监测研究.中华检验医学杂志,2005, 28(3):254-265
[7]朱德妹,张婴元,汪复等.2008年上海地区细菌耐药性监测.中国感染与化疗杂志,2009,9(6):401-411
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[10] Berger-Bachi B, Rohrer S. Factors influencing methicillin resistance in staphylococci. Arch. Microbiol. 2002,178(3): 165-171.
[11] Stapleton PD, Taylor PW. Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. Sci Prog 2002, 85 (1):57-72.
[12] Henze, U.U. and B. Berger-Bachi, Penicillin-binding protein 4 overproduction increases beta-lactam resistance in Staphylococcus aureus. Antimicrob Agents Chemother, 1996. 40(9): p. 2121-5.
[13]Stranden AM, Ehlert K, Labischinski H, Berger-Bachi B. Cell wall monoglycinecross-bridges and methicillin hypersusceptibility in a femAB null mutant of methicillin-resistant Staphylococcus aureus. J Bacteriol 1997,179 (1):9-16.
[14] Chambers H F. Methicillin Resistance in Staphylococci: Molecular and Biochemical Basis and Clinical Implications. Clinical Microbiology Reviews, 1997, 10 (4):781-791
[15] Fujimura T and Murakami K. A high-level methicillin-resistant clinical isolate of Staphylococcus aureus with lytH mutation caused by IS1182 insertion. Antimicrob. Agents Chemother. 2007, 52 (2):643-647
[16] Trotonda MP, Xiong YQ, Memmi G, Bayer AS, Cheung, AL. Role of mgrA and sarA in methicillin-resistant Staphylococcus aureus autolysis and resistance to cell wall-active antibiotics. J Infect Dis. 2009,199(2):209-218
[17]杜锐,韩文瑜,雷连成.金黄色葡萄球菌氟喹诺酮的耐药性与gyrA、gyrB突变的关系研究.中国预防兽医学报,2006,28(4):415～418.
[18]黄支密,陆亚华,诸葛青云,单浩,邹玉秀,熊春林.多重耐药MRSA耐消毒剂基因及抗生素耐药相关基因检测.中国抗生素杂志,2005,30(5):270～273
[19]顾觉奋,李振国.耐万古霉素金葡菌及抗VRSA感染药物的研究进展.抗感染药学,2009,6(2):73-76
[20] Sievert DM, Rudrik JT, Patel JB, et al. Vancomycin-resistant Staphylococcus aureus in the United States, 2002– 2006. Clin Infect Dis, 2008, 46 (5): 668 - 674.
[21] Zurenko GE, Gibson JK, Shinabarger DL, et al. Oxazolidinones: a new class of antibacterials. Current Pharmaceutical Design, 2001, 1 (5): 470–476.
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[29] Lee JW, Ji YJ, Lee SO, et al. Effect of Saliva miltiorrhiza Bunge on antimicrobial activity and resistant gene regulation against Methicillin-resistant Staphylococcus aureus(MRSA).J Microb. 2007, 45 (4):350-357
[30] Yu HH, Kim KJ, Cha JD, et al. Antimicrobial Activity of Berberine Alone and in Combination with Ampicillin or Oxacillin Against Methicillin-Resistant Staphylococcus aureus. J Med Food,2005, 8(4): 454-461
[31] Liu IX , Durham DG, Richards RM .Baicalin synergy with beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus and other beta-lactam-resistant strains of S. aureus. J Pharm Pharmacol, 2000, 52(3): 361-366
[32] Fujita M, Shiota S, Kuroda T,et al. Remarkable synergies between baicalein and tetracycline, and baicalein and beta-lactams against methicillin-resistant Staphylococcus aureus. Microbiol Immunol, 2005. 49(4): 391-396.
[33]唐敏,刘耀,王渝,李由页,夏培元.金银花总黄酮粗提物体外抑菌作用研究.中药研究,2008,19(30):2321-2322
[2]徐振波,石磊.葡萄球菌属中交换基因的载体——SCCmec.中国抗生素杂志,2007,32(8):449-453
[3] Berglund C, Ito T, Ikeda M, Ma XX, Soderquist B, Hiramatsu K (2008). Novel type of staphylococcal cassette chromosome mec in a methicillin-resistant Staphylococcus aureus strain isolated in Sweden. Antimicrob. Agents Chemother. 52: 3512-3516.
[4] Deurenberg RH, Stobberingh EE. The evolution of Staphylococcus aureus. Infect. Genet. Evol.2008, 8: 747-763.
[5] Higuchi W, Takano T, Teng LJ, Yamamoto T. Structure and specific detection of staphylococcal cassette chromosome mec type VII. Biochem. Biophys. Res. Commun. 2008, 377: 752-756.
[6] Oliveira DC, de Lencastre H. Multiplex PCR strategy for rapid identification of structural types and variants of the mec element in methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2002,46:2155-2161.
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[8] Robinson DA, Enright MC. Evolutionary models of the emergence of methicillin-resistant Staphylococcus aureus. Antimicrob. AgentsChemother. 2003, 47: 3926-3934.
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[10]朱德妹,张婴元,汪复等.2008年上海地区细菌耐药性监测.中国感染与化疗杂志.2009,9(6):401-411
[11]李家泰,齐慧敏,李耘. 2002-2003年中国医院和社区获得性感染革兰阳性细菌耐药监测研究.中华检验医学杂志, 2005, 28(3):254-265.
[12] Zhao WH, Hu ZQ, Okubo S, Hara Y, Shimamura T. Mechanism of synergy between epigallocatechin gallate and beta-lactams against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2001,45(6): 1737-1742.
[13] Clinical and Laboratory Standards Institute.(2009). M100-S19. Performance standards for antimicrobial susceptibility testing; nineteenth informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA
[14] Kim J, Jeong JH, Cha HY, Jin JS, Lee JC, Lee YC, Seol SY, Cho DT. Detection of diverse SCCmec variants in methicillin-resistant Staphylococcus aureus and comparison of SCCmec typing methods. Clin. Microbiol. Infect. 2007,13(11): 1128-1130.
[15] Baddour MM., Abuelkheir MM, Fatani AJ. Trends in antibioticsusceptibility patterns and epidemiology of MRSA isolates from several hospitals in Riyadh, Saudi Arabia. Ann. Clin. Microbiol. Antimicrob. 2006,5: 30.
[16] Berger-Bachi B, Rohrer S. Factors influencing methicillin resistance in staphylococci. Arch. Microbiol. 2002,178(3): 165-171.
[17] Stapleton PD, Taylor PW. Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. Sci Prog 2002, 85 (1):57-72.
[18] Henze UU, Berger-Bachi B. Penicillin-binding protein 4 overproduction increases beta-lactam resistance in Staphylococcus aureus. Antimicrob Agents Chemother 1996,40 (9):2121-5.
[19] Stranden AM, Ehlert K, Labischinski H, Berger-Bachi B. Cell wall monoglycinecross-bridges and methicillin hypersusceptibility in a femAB null mutant of methicillin-resistant Staphylococcus aureus. J Bacteriol 1997,179 (1):9-16.
[20] Chambers H F. Methicillin Resistance in Staphylococci: Molecular and Biochemical Basis and Clinical Implications. Clinical Microbiology Reviews, 1997, 10 (4):781-791
[21] Fujimura T and Murakami K. A high-level methicillin-resistant clinical isolate of Staphylococcus aureus with lytH mutation caused by IS1182 insertion. Antimicrob. Agents Chemother. 2007,52(2):643-647
[22] Trotonda MP, Xiong YQ, Memmi G, Bayer AS, Cheung, AL. Role of mgrAand sarA in methicillin-resistant Staphylococcus aureus autolysis and resistance to cell wall-active antibiotics. J Infect Dis. 2009,199(2):209-218
[23]杜锐,韩文瑜,雷连成.金黄色葡萄球菌氟喹诺酮的耐药性与gyrA、gyrB突变的关系研究.中国预防兽医学报,2006,28(4):415～418.
[24]黄支密,陆亚华,诸葛青云,单浩,邹玉秀,熊春林.多重耐药MRSA耐消毒剂基因及抗生素耐药相关基因检测.中国抗生素杂志,2005,30(5):270～273
[25]梁锦湄,梁蓓蓓,王睿.耐甲氧西林金葡球菌的研究进展.中国新药杂志,2008, 17(13):1097-1100
[26]顾觉奋,李振国.耐万古霉素金葡菌及抗VRSA感染药物的研究进展.抗感染药学,2009,6(2):73-76
[27] Sievert DM, Rudrik JT, Patel JB, et al. Vancomycin-resistant S taphylococcus aureus in the United States, 2002– 2006. Clin Infect D is, 2008, 46 (5) : 668 - 674.
[28]Baddour MM., Abuelkheir MM, Fatani AJ. Trends in antibiotic susceptibility patterns and epidemiology of MRSA isolates from several hospitals in Riyadh, Saudi Arabia. Ann. Clin. Microbiol. Antimicrob. 2006, 5: 30
[29]Cha HY, Moon DC, Choi CH,et al. Prevalence of the ST239 clone of methicillin-resistant Staphylococcus aureus and differences in antimicrobial susceptibilities of ST239 and ST5 clones identifiedin a Korean hospital. J Clin. Microbiol. 2005,43: 3610-3614.
[30] Cunha BA. New uses for older antibiotics: nitrofurantoin, amikacin, colistin, polymyxin B, doxycycline, and minocycline revisited. Med. Clin. North. Am. 2006, 90: 1089-1107.
[31] Kim HB, Jang HC, Nam HJ, et al. In vitro activities of 28 antimicrobial agents against Staphylococcus aureus isolates from tertiary-care hospitals in Korea: a nationwide survey. Antimicrob. Agents Chemother. 2004, 48:1124-1127.
[32] Ko KS, Lee JY, Suh JY,et al. Distribution of major genotypes among methicillin-resistant Staphylococcus aureus clones in Asian countries. J. Clin. Microbiol. 2005,43: 421-426.
[33] Fatholahzadeh B, Emaneini M, Gilbert G., et al. Staphylococcal cassette chromosome mec (SCCmec) analysis and antimicrobial susceptibility patterns of methicillin-resistant Staphylococcus aureus (MRSA) isolates in Tehran, Iran. Microb. Drug. Resist. 2008,14: 217-220.
[34] Kilic A, Guclu AU, Senses Z, Bedir O, Aydogan H, Basustaoglu AC. Staphylococcal cassette chromosome mec (SCCmec) characterization and panton-valentine leukocidin gene occurrence for methicillin-resistant Staphylococcus aureus in Turkey, from 2003 to 2006. Antonie. Van. Leeuwenhoek. 2008, 94: 607-614.
[35] Faria NA, Carrico JA,Oliveira DC.Analysis of typing methods forepidemiological surveillance of both methicillin-resistant and methicillin-susceptible Staphylococcus aureus strains. J Clin Microbiol.2008,46(1):136-144
[1] Lee JW, Ji YJ, Lee SO, et al. Effect of Saliva miltiorrhiza bunge on antimicrobial activity and resistant gene regulation against methicillin-resistant Staphylococcus aureus (MRSA). J Microbiol, 2007, 45(4): 350-7.
[2] Yu HH, Kim KJ, Cha JD, et al. Antimicrobial activity of berberinealone and in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. J Med Food, 2005,8(4): 454-461.
[3] Fujita M, Shiota S, Kuroda T, et al. Remarkable synergies between baicalein and tetracycline, and baicalein and beta-lactams against methicillin-resistant Staphylococcus aureus. Microbiol Immunol, 2005, 49(4): 391-396.
[4] Yu L, Xiang H, Fan J, et al. Global transcriptional response of Staphylococcus aureus to rhein, a natural plant product. J Biotechnol, 2008,135(3): 304-308.
[5] Feng H, Xiang H, Zhang J, et al. Genome-wide transcriptional profiling of the response of Staphylococcus aureus to cryptotanshinone. J Biomed Biotechnol, 2009,2009: 617509.
[6] Stapleton PD, Shah S, Ehlert K, et al. Theβ-lactam-resistance modifier (-)-epicatechin gallate alters the architecture of the cell wall of Staphylococcus aureus. Microbiology, 2007,153(7): 2093-2103.
[7] Sieradzki, K. and A. Tomasz, Inhibition of the autolytic system by vancomycin causes mimicry of vancomycin-intermediate Staphylococcus aureus-type resistance, cell concentration dependence of the MIC, and antibiotic tolerance in vancomycin-susceptible S. aureus. Antimicrob Agents Chemother,2006,50(2): 527-533.
[8] Sieradzki, K. and A. Tomasz, Inhibition of cell wall turnover and autolysis by vancomycin in a highly vancomycin-resistant mutant of Staphylococcus aureus. J Bacteriol, 1997,179(8): 2557-2566.
[9] Sieradzki K, Tomasz A. Inhibition of the autolytic system by vancomycin causes mimicry of vancomycin-intermediate Staphylococcus aureus-type resistance,cell concentration dependence of the MIC,and antibiotic tolerance in vancomycin- susceptible S.aureus. Antimicrob Agents Chemother, 2006,50(2): 527-533.
[10] Chambers HF. Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications. Clin Microbiol Rev, 1997,10(4): 781-91.
[11] Parvez MA, Shibata H, Nakano T, et al. No relationship exists between PBP 2a amounts expressed in different MRSA strains obtained clinically and their beta-lactam MIC values. J Med Invest, 2008, 55(3-4): 246-253.
[12] Pereira SF, Henriques AO, Pinho MG, et al. Role of PBP1 in cell division of Staphylococcus aureus. J Bacteriol, 2007,189(9): 3525-3531.
[13] Pereira SF, Henriques AO, Pinho MG, et al. Evidence for a dual role of PBP1 in the cell division and cell separation of Staphylococcusaureus. Mol Microbiol, 2009,72(4): 895-904.
[14] Henze UU and Berger-Bachi B. Penicillin-binding protein 4 overproduction increases beta-lactam resistance in Staphylococcus aureus. Antimicrob Agents Chemother, 1996,40(9): 2121-2125.
[15] Stapleton PD. and Taylor PW. Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. Sci Prog, 2002,85(Pt 1): 57-72.
[16] Putman M, van Veen HW, Konings WN. Molecular properties of bacterial multidrug transporters. Microbiol Mol Biol Rev, 2000 , 64(4): 672-93.
[17] Davidson, A.L., et al., Structure, function, and evolution of bacterial ATP-binding cassette systems. Microbiol Mol Biol Rev, 2008,72(2): 317-364.
[18] Braun V. Bacterial iron transport related to virulence. Contrib Microbiol, 2005,12: 210-33.
[19] Davidson AL, Dassa E, Orelle C, et al. DNA helicase activity of PcrA is not required for the displacement of RecA protein from DNA or inhibition of RecA-mediated strand exchange. J Bacteriol, 2007,189(12): 4502-4509.
[20] Chang TL, Naqvi A, Anand SP, et al. Biochemical characterization of the Staphylococcus aureus PcrA helicase and its role in plasmid rolling circle replication. J Biol Chem, 2002,277(48): 45880-6.
[21] Lusetti SL, Cox MM. The bacterial RecA protein and the recombinational DNA repair of stalled replication forks. Annu Rev Biochem, 2002,71: 71-100.
[22] Rodnina MV, Beringer M, Wintermeyer W. How ribosomes make peptide bonds. Trends Biochem Sci, 2007,32(1): 20-26.
[23] Antignac A, Sieradzki K, Tomasz A. Perturbation of cell wall synthesis suppresses autolysis in Staphylococcus aureus: evidence for coregulation of cell wall synthetic and hydrolytic enzymes. J Bacteriol, 2007,189(21): 7573-7580.
[24] Tomasz A, Waks S. Mechanism of action of penicillin: triggering of the pneumococcal autolytic enzyme by inhibitors of cell wall synthesis. Proc Natl Acad Sci, 1975,72(10): 4162-4166.
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