松鼠葡萄球菌mecA和金黄色葡萄球菌mecA在松鼠葡萄球菌耐药机制及细胞壁合成中的作用
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摘要
金黄色葡萄球菌是引起医院内获得性感染和社区获得性感染的重要致病菌之一。β-内酰胺类抗生素曾经是治疗金黄色葡萄球菌感染的有效武器，但随着耐甲氧西林的金黄色葡萄球菌(Methicillin resistant Staphylococcus aureus，MRSA)分离率的逐渐增加，金黄色葡萄球菌引起的感染成为临床上非常棘手的问题。耐药的主要决定基因为mecA。mecA编码的青霉素结合蛋白2A(penicillin-binding protein 2A，PBP2A)对β-内酰胺类抗生素亲和力很低，当固有的PBP被β-内酰胺类抗生素饱和时，PBP2A可替代这些PBPs的转肽功能催化细胞壁合成。mecA基因并非金黄色葡萄球菌的固有基因，而是一外源基因，其来源有很多假设，目前认为是从松鼠葡萄球菌中获得。大多数松鼠葡萄球菌的mecA并不提供抗药性，但把活化的松鼠葡萄球菌mecA引入到敏感的金黄色葡萄球菌可使后者的抗药性大大增加，松鼠葡萄球菌的mecA基因产物能够利用金黄色葡萄球菌的细胞壁前体合成金黄色葡萄球菌的细胞壁。最近，我们分离到了既含有松鼠葡萄球菌的mecA又含有金黄色葡萄球菌的mecA的松鼠葡萄球菌K3，K3为黄色菌落，在没有抗生素存在时能自发分化为K3y(黄色菌落)和K3w(白色菌落)。前者表型和基因型与亲代菌完全相同，后者仅含有松鼠葡萄球菌mecA而丢失了金黄色葡萄球菌的mecA。本论文将针对这两个mecA基因在松鼠葡萄球菌的耐药性及细胞壁合成中的作用进行研究。
目的：进一步研究松鼠葡萄球菌的生物学特征和基因特征以期更深入的理解金黄色葡萄球菌耐药性基因mecA来源以及MRSA菌株的耐药机制；同时，认识临床上分离率日益增加的松鼠葡萄球菌的耐药机制。方法：通过抗生素压力选择出松鼠葡萄球菌K3的高度均一耐药株；应用E-test和PAP试验来检测松鼠葡萄球菌对苯唑西林的耐药性；PCR扩增两个mecA基因并制备DNA探针；多重PCR用于菌株K3和K8的SCCmec分型；应用Northern blot和Western blot分别检测两个mecA基因在转录水平和蛋白质水平上的表达；通过克隆和测序排布出敏感菌K1及耐药菌K3 orfX区的基因分布，与GenBank中的同源序列进行比较并分析其特征；SmaⅠ消化染色体DNA后，脉冲场电泳分离消化产物，Southern blot检测orfX和mecA在染色体上的位置关系；分离、纯化细菌膜蛋白后应用PBP assay鉴定出松鼠葡萄球菌的青霉素结合蛋白图谱以及各个PBPs对β-内酰胺类抗生素的亲和力；分离、纯化细胞壁，高压液相法分析细胞壁成分。
结果：经过抗生素选择压力，筛选出K3的homo*衍生菌K3HO，K3HW，K3HWO。K3对苯唑西林呈异质性耐药，K3 homo*衍生菌对苯唑西林高度均一耐药，MIC＞400μg／ml。在抗生素存在的情况下，K3自发分化为K3w和K3y的现象被抑制，分化出的黄，白菌落均含有松鼠葡萄球菌mecA和金黄色葡萄球菌mecA。同时，金黄色葡萄球菌的mecA被大量诱导，但Northern blot检测不到松鼠葡萄球菌mecA的表达。K3 homo*衍生菌的金黄色葡萄球菌mecA表达轻微提高，但也未能检测到松鼠葡萄球菌mecA在RNA水平的表达。K3和K8分别为SCCmecⅢB和SCCmecⅢA型，SCCmec准确的插入到orfX区。K1和K3 orfX区的基因排布和表皮葡萄球菌和溶血葡萄球菌相似而和金黄色葡萄球菌差异较大。orfX和mecA基因在染色体上的位置随菌株不同而不同。鉴定了6种PBPs，其中PBP4即为松鼠葡萄球菌mecA的表达产物，对苯唑西林呈低亲和力。PBP6在苯唑西林耐药性方面可能发挥了重要作用。苯唑西林耐药菌细胞壁交联率高于敏感菌，但交联率的高低和菌株的MIC值并不呈线形关系。在抗生素压力下，金黄色葡萄球菌的mecA产物能利用松鼠葡萄球菌细胞壁合成前体合成松鼠葡萄球菌的细胞壁。结论：在两个mecA共存的松鼠葡萄球菌中，金黄色葡萄球菌mecA和抗药性直接相关，但也不能排除松鼠葡萄球菌mecA的作用。orfX和mecA位于基因重组的热点或附近，这有利于松鼠葡萄球菌获得新的SCCmec或松鼠葡萄球菌mecA的转移。松鼠葡萄球菌细胞壁的高度交联率和耐药性相关，这不同于敏感和耐药的金黄色葡萄球菌细胞壁特征。松鼠葡萄球菌的mecA和金黄色葡萄球菌mecA在细胞壁的合成中具有相互替代性。
Staphylococcus aureus (S. aureus) is a versatile and dangerous pathogen in humans. In the past,β-lactam antibiotics were powerful weapons to treat infections caused by staphylococci. However, treatment of these infections had stumbled since the emergence of methicillin-resistant S. aureus (MRSA). The genetic determinant of methicillin resistance in MRSA is mecA, which encodes the low-affinity penicillin-binding protein 2A (PBP2A). PBP2A takes over the transpeptidase role of the normal penicillin-binding proteins (PBPs) in the presence of oxacillin, thus continuing the process of cell wall synthesis. The mecA gene that is carried by SCCmec vehicle is not an original gene of MRSA and speculated to be evolved from the species of Staphylococcus sciuri (S. sciuri) in staphylococcal genus. S. sciuri belongs to coagulase-negative staphylococci (CNS) and is generally considered one of the most primitive staphylococcal species. It is distantly related to S. aureus along taxonomic lines. One hundred thirty four independent and genetically diverse S. sciuri isolates were each found to carry the mecA homologue, yet most of the mecA homologues do not confer resistance to antibiotics. Further study showed the laboratory S. sciuri mutant selected by methicillin was highly resistant to methicillin duo to a point mutation in the mecA promoter. Introduction of the activated S. sciuri mecA into S. aureus led to the increase of antibiotic resistance. The imported S. sciuri mecA was involved in the process of cell wall synthesis of the host strain of S. aureus. Recently, a clinical S. sciuri isolate K3 harboring both S. sciuri mecA and S. aureus mecA was isolated and showed resistance to methicillin. K3 strain was unstable in the absence of drug selection and tended to segregate into K3w accompanied by the loss of S. aureus mecA and K3y which had the same phenotypic and genetic characters as parental strain. This result promotes us to characterize the roles of S. sciuri mecA and S. aureus mecA in theβ-lactam antibiotic resistance and cell wall synthesis.
Objective: To identify biological and genetic characteristics of S. sciuri strains and give insights into the evolution of the mecA gene in the MRSA strain as well as the mechanism(s) of methicillin resistance in staphylococci; To clarify the molecular mechanisms of antibiotic resistance among the increasingly isolated multiple-drug resistant strains of S. sciuri, which would provide useful information for clinical researches. Method: K3 containing both S. sciuri mecA and S. aureus mecA was the main strain used in this thesis. Isolates representing three subspecies of S. sciuri were also included in different experiments. Homo* derivatives of K3 were obtained after antibiotic selection. Antibiotic susceptibility profiles of the strains were analyzed by E-test and population analysis profiles (PAP). PCR was used to amplify two mecA genes and prepare all the probes; SCCmec typing was determined by multiple PCR. Expression of mecA genes were studied by Northern blot and Western blot; The genetic organization of orfX region was identified by cloning and sequencing; The putative function of the newly-identified genes was revealed by comparing with the homologues in GenBank; Detection of variations of orfX and mecA genes in chromosomal location was performed by pulse field with Sma I digestion and Southern blot; Penicillin-binding proteins were identified and characterized by PBP flurographic assay; High-pressure liquid chromatography was used to analyze the compositions of cell wall. Result: K3 strain carrying two copies of mecA genes confered heterogenous resistance to oxacillin. Segregation of antibiotic-susceptible cells K3w containing one copy of S. sciuri mecA was inhibited under oxaicllin pressure. Strains K3HO, K3HW, and K3HWO which were derived from K3 strain showed homogenous resistance to oxacillin. Expression of S. aureus mecA was highly induced in K3 strain with oxacillin and expression of S. sciuri mecA was not detectable by Northern blot. Slightly increase was detected in K3 homo* derivatives. K3 belonged to SCCmecⅢB and its SCCmec was precisely integrated in the orfX region. The genetic locations of S. sciuri mecA and orfX gene varied strain by strain. Six PBPs were identified in S. sciuri strains. PBP4 was only detected in oxacillin resistant S. sciuri strains and it was the genetic product of S. sciuri rnecA and showed low-affinity to oxacillin. These observations implied that PBP4 may be responsible for the resistance in oxacillin resistant S. sciuri strains. Furthermore, PBP6 was also determined to be a major PBP in conferring oxacillin resistance since the enhancement of PBP6 in oxacillin resistant strain K1M200 and the loss of PBP6 in K3w along with the decreased MIC comparing with parental strain K3. Cross-linking degree of cell wall in oxacillin-susceptible S. sciuri strains was 27.9% for K1 strain and 29.1% for K3w strain whereas the cross-linking rate was increased to 36.6% in K3, 36.7% in strain K3HO, 37.7% in strain SS-37 and 59.8% in strain K1M200. There was no proportional relationship between cross-linking degree and MIC value. In the presence of oxacillin, S. aureus mecA was expressed dominantly in K3 strain and the product serving as transpeptidase can use the cell wall precursor of S. sciuri to synthesize the S. sciuri type of cell wall. Conclusion: S. aureus mecA was more likely to respond to antibiotic pressure and confered resistance to the S. sciuri host. Nevertheless, S. sciuri mecA was not so silent as we thought, orfX and S. sciuri mecA genes were located at hotspots for genetic recombination, which might favor the bacteria for adoption of SCCmec and donation of S. sciuri mecA. The species of S. sciuri would have more options in development of resistance toβ-lactam antibiotics depending on the special relationship with the two mecA genes. Cross-linking degree was higher in oxacillin resistant S. sciuri strains than oxacillin susceptible S. sciuri strains. S. aureus mecA and S. sciuri mecA were functionally interchangeable in the cell wall synthesis.
目的：进一步研究松鼠葡萄球菌的生物学特征和基因特征以期更深入的理解金黄色葡萄球菌耐药性基因mecA来源以及MRSA菌株的耐药机制；同时，认识临床上分离率日益增加的松鼠葡萄球菌的耐药机制。方法：通过抗生素压力选择出松鼠葡萄球菌K3的高度均一耐药株；应用E-test和PAP试验来检测松鼠葡萄球菌对苯唑西林的耐药性；PCR扩增两个mecA基因并制备DNA探针；多重PCR用于菌株K3和K8的SCCmec分型；应用Northern blot和Western blot分别检测两个mecA基因在转录水平和蛋白质水平上的表达；通过克隆和测序排布出敏感菌K1及耐药菌K3 orfX区的基因分布，与GenBank中的同源序列进行比较并分析其特征；SmaⅠ消化染色体DNA后，脉冲场电泳分离消化产物，Southern blot检测orfX和mecA在染色体上的位置关系；分离、纯化细菌膜蛋白后应用PBP assay鉴定出松鼠葡萄球菌的青霉素结合蛋白图谱以及各个PBPs对β-内酰胺类抗生素的亲和力；分离、纯化细胞壁，高压液相法分析细胞壁成分。
结果：经过抗生素选择压力，筛选出K3的homo*衍生菌K3HO，K3HW，K3HWO。K3对苯唑西林呈异质性耐药，K3 homo*衍生菌对苯唑西林高度均一耐药，MIC＞400μg／ml。在抗生素存在的情况下，K3自发分化为K3w和K3y的现象被抑制，分化出的黄，白菌落均含有松鼠葡萄球菌mecA和金黄色葡萄球菌mecA。同时，金黄色葡萄球菌的mecA被大量诱导，但Northern blot检测不到松鼠葡萄球菌mecA的表达。K3 homo*衍生菌的金黄色葡萄球菌mecA表达轻微提高，但也未能检测到松鼠葡萄球菌mecA在RNA水平的表达。K3和K8分别为SCCmecⅢB和SCCmecⅢA型，SCCmec准确的插入到orfX区。K1和K3 orfX区的基因排布和表皮葡萄球菌和溶血葡萄球菌相似而和金黄色葡萄球菌差异较大。orfX和mecA基因在染色体上的位置随菌株不同而不同。鉴定了6种PBPs，其中PBP4即为松鼠葡萄球菌mecA的表达产物，对苯唑西林呈低亲和力。PBP6在苯唑西林耐药性方面可能发挥了重要作用。苯唑西林耐药菌细胞壁交联率高于敏感菌，但交联率的高低和菌株的MIC值并不呈线形关系。在抗生素压力下，金黄色葡萄球菌的mecA产物能利用松鼠葡萄球菌细胞壁合成前体合成松鼠葡萄球菌的细胞壁。结论：在两个mecA共存的松鼠葡萄球菌中，金黄色葡萄球菌mecA和抗药性直接相关，但也不能排除松鼠葡萄球菌mecA的作用。orfX和mecA位于基因重组的热点或附近，这有利于松鼠葡萄球菌获得新的SCCmec或松鼠葡萄球菌mecA的转移。松鼠葡萄球菌细胞壁的高度交联率和耐药性相关，这不同于敏感和耐药的金黄色葡萄球菌细胞壁特征。松鼠葡萄球菌的mecA和金黄色葡萄球菌mecA在细胞壁的合成中具有相互替代性。
Staphylococcus aureus (S. aureus) is a versatile and dangerous pathogen in humans. In the past,β-lactam antibiotics were powerful weapons to treat infections caused by staphylococci. However, treatment of these infections had stumbled since the emergence of methicillin-resistant S. aureus (MRSA). The genetic determinant of methicillin resistance in MRSA is mecA, which encodes the low-affinity penicillin-binding protein 2A (PBP2A). PBP2A takes over the transpeptidase role of the normal penicillin-binding proteins (PBPs) in the presence of oxacillin, thus continuing the process of cell wall synthesis. The mecA gene that is carried by SCCmec vehicle is not an original gene of MRSA and speculated to be evolved from the species of Staphylococcus sciuri (S. sciuri) in staphylococcal genus. S. sciuri belongs to coagulase-negative staphylococci (CNS) and is generally considered one of the most primitive staphylococcal species. It is distantly related to S. aureus along taxonomic lines. One hundred thirty four independent and genetically diverse S. sciuri isolates were each found to carry the mecA homologue, yet most of the mecA homologues do not confer resistance to antibiotics. Further study showed the laboratory S. sciuri mutant selected by methicillin was highly resistant to methicillin duo to a point mutation in the mecA promoter. Introduction of the activated S. sciuri mecA into S. aureus led to the increase of antibiotic resistance. The imported S. sciuri mecA was involved in the process of cell wall synthesis of the host strain of S. aureus. Recently, a clinical S. sciuri isolate K3 harboring both S. sciuri mecA and S. aureus mecA was isolated and showed resistance to methicillin. K3 strain was unstable in the absence of drug selection and tended to segregate into K3w accompanied by the loss of S. aureus mecA and K3y which had the same phenotypic and genetic characters as parental strain. This result promotes us to characterize the roles of S. sciuri mecA and S. aureus mecA in theβ-lactam antibiotic resistance and cell wall synthesis.
Objective: To identify biological and genetic characteristics of S. sciuri strains and give insights into the evolution of the mecA gene in the MRSA strain as well as the mechanism(s) of methicillin resistance in staphylococci; To clarify the molecular mechanisms of antibiotic resistance among the increasingly isolated multiple-drug resistant strains of S. sciuri, which would provide useful information for clinical researches. Method: K3 containing both S. sciuri mecA and S. aureus mecA was the main strain used in this thesis. Isolates representing three subspecies of S. sciuri were also included in different experiments. Homo* derivatives of K3 were obtained after antibiotic selection. Antibiotic susceptibility profiles of the strains were analyzed by E-test and population analysis profiles (PAP). PCR was used to amplify two mecA genes and prepare all the probes; SCCmec typing was determined by multiple PCR. Expression of mecA genes were studied by Northern blot and Western blot; The genetic organization of orfX region was identified by cloning and sequencing; The putative function of the newly-identified genes was revealed by comparing with the homologues in GenBank; Detection of variations of orfX and mecA genes in chromosomal location was performed by pulse field with Sma I digestion and Southern blot; Penicillin-binding proteins were identified and characterized by PBP flurographic assay; High-pressure liquid chromatography was used to analyze the compositions of cell wall. Result: K3 strain carrying two copies of mecA genes confered heterogenous resistance to oxacillin. Segregation of antibiotic-susceptible cells K3w containing one copy of S. sciuri mecA was inhibited under oxaicllin pressure. Strains K3HO, K3HW, and K3HWO which were derived from K3 strain showed homogenous resistance to oxacillin. Expression of S. aureus mecA was highly induced in K3 strain with oxacillin and expression of S. sciuri mecA was not detectable by Northern blot. Slightly increase was detected in K3 homo* derivatives. K3 belonged to SCCmecⅢB and its SCCmec was precisely integrated in the orfX region. The genetic locations of S. sciuri mecA and orfX gene varied strain by strain. Six PBPs were identified in S. sciuri strains. PBP4 was only detected in oxacillin resistant S. sciuri strains and it was the genetic product of S. sciuri rnecA and showed low-affinity to oxacillin. These observations implied that PBP4 may be responsible for the resistance in oxacillin resistant S. sciuri strains. Furthermore, PBP6 was also determined to be a major PBP in conferring oxacillin resistance since the enhancement of PBP6 in oxacillin resistant strain K1M200 and the loss of PBP6 in K3w along with the decreased MIC comparing with parental strain K3. Cross-linking degree of cell wall in oxacillin-susceptible S. sciuri strains was 27.9% for K1 strain and 29.1% for K3w strain whereas the cross-linking rate was increased to 36.6% in K3, 36.7% in strain K3HO, 37.7% in strain SS-37 and 59.8% in strain K1M200. There was no proportional relationship between cross-linking degree and MIC value. In the presence of oxacillin, S. aureus mecA was expressed dominantly in K3 strain and the product serving as transpeptidase can use the cell wall precursor of S. sciuri to synthesize the S. sciuri type of cell wall. Conclusion: S. aureus mecA was more likely to respond to antibiotic pressure and confered resistance to the S. sciuri host. Nevertheless, S. sciuri mecA was not so silent as we thought, orfX and S. sciuri mecA genes were located at hotspots for genetic recombination, which might favor the bacteria for adoption of SCCmec and donation of S. sciuri mecA. The species of S. sciuri would have more options in development of resistance toβ-lactam antibiotics depending on the special relationship with the two mecA genes. Cross-linking degree was higher in oxacillin resistant S. sciuri strains than oxacillin susceptible S. sciuri strains. S. aureus mecA and S. sciuri mecA were functionally interchangeable in the cell wall synthesis.
引文
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