高盐条件下耐盐真菌的次生代谢产物研究
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摘要
高盐微生物是一类极端微生物,可生存在高盐环境中。由于其生存环境的特殊性,可能具有独特的次生代谢途径,产生特有的次生代谢产物,是一类重要的天然产物研究资源。特别是将生物学与化学相结合,在生物学菌种分离纯化,菌种鉴定以及发酵条件摸索的基础上,利用化学手段对高盐微生物次生代谢产物的化学多样性进行研究,从高盐微生物次生代谢产物中寻找抗肿瘤抗菌等活性的先导化合物。
本论文从采自海南文昌清澜红树林保护区和广西山口红树林保护区的红树植物的叶和根部样品中获得3株耐盐天才真菌,从来源于海南临高附近海域的蕾二岐灯芯柳珊瑚的筛选到1株耐盐天才真菌；对这4株菌在盐胁迫条件下产生的次生代谢产物进行了系统研究,并就盐胁迫对耐盐天才真菌次生代谢产物化学多样性的影响做了探讨。
研究内容主要包括以下3个方面：
1.耐盐天才真菌的筛选。从来源于红树林高盐环境的样品中分离纯化获得133株耐盐真菌。以P388肿瘤细胞增殖抑制、抑菌试验作为生物活性筛选模型,TLC薄层色谱和HPLC指纹图谱作为化学筛选模型,采用生物活性和化学评价相结合的集成筛选模式,最终获得3株耐盐天才真菌。从来源于海南临高附近海域的蕾二岐灯芯柳珊瑚的筛选到1株耐盐天才真菌。
2.盐胁迫诱导下的4株耐盐天才真菌次生代谢产物的研究。对耐盐天才真菌进行发酵条件摸索,如培养基、发酵天数、盐度等,选择最佳培养条件进行大发酵,获得发酵浸膏。通过薄层色谱、硅胶柱色谱、Sephadex LH-20柱色谱、反相高效液相色谱等分离方法,从盐胁迫诱导的4株耐盐天才真菌次生代谢产物中,共分离得到78个单体化合物；应用波谱解析(UV, IR, NMR, MS, X-Ray等)和化学方法鉴定了72个单体化合物的化学结构。其中新化合物23个：从耐盐真菌赭曲霉Aspergillus ochraceus P-Z高盐条件代谢产物中获得了7个新的毗嗪酰胺类生物碱和线性四肽(3-9)；从枝孢样枝孢霉霉Cladosporium cladosporioides PXP-49高盐条件代谢产物中得到8个新的不饱和脂肪酸(酯)类化合物(12-19)；从产黄青霉Penicillium chrysogenum PXP-55高盐条件代谢产物中得到5个新的神经鞘胺醇糖苷类化合物(30-34)和2个新的2-吡啶酮类生物碱(35,36)；从耐盐真菌Wallemia sebi PXP-89高盐条件代谢产物中得到1个新的吡啶生物碱(44)。已知化合物的结构类型涉及苯的衍生物、脂肪酸类化合物、大环内酯类、甾体类化合物、呋哺衍生物和环二肽类化合物等。运用体外生物活性筛选模型,评价了新化合物的肿瘤细胞增殖抑制活性和抑菌活性。抑菌活性结果表明：吡嗪酰胺类和线性四肽类化合物4、8和9,神经鞘胺醇糖苷类化合物31,毗啶衍生物44对产气杆菌均具有抑制作用,MIC分别为40、20.1、18.9、1.72和76.7,μM；化合物8对金黄色葡萄球菌具有抑制作用(MIC,98μM),且这些化合物均为含氮化合物。
3.初步评价了卤盐胁迫对耐盐真菌次生代谢产物化学多样性的影响。使用对代谢产量、TLC、HPLC指纹图谱及生物活性作比较等方法,对高盐胁迫条件下6株耐盐真菌次生代谢产物的特点做了分析,利用该方法得到了一株在高盐条件下产生亮氨酸途径合成的线性四肽(8,9)的耐盐真菌(P-Z),证实了微生物的次生代谢存在卤盐效应。
综上所述,通过对耐盐天才真菌在高盐胁迫条件下次生代谢产物的系统研究,证实了盐胁迫能够增加耐盐微生物的化学多样性,产生新的活性含氮化合物,并为海洋药用微生物资源的开发提供了重要的参考。
Halotolerant microbe is one of extreme microorganism which can survive in high salt environment. Because of its specificity of living environment, halotolerant microbe may have unique secondary metabolic pathways and produce the unique secondary metabolites. Halotolerant microbe is an important class of resources for natural products. By integrated biological and chemical screening methods, talented strains with potential to produce chemically diverse secondary metabolites could be easily discovered. Further, the lead compounds with antitumor and antibiotic activity might be found from microbial secondary metabolites through optimization of the culture condition under high salt stress.
This dissertation focuses on the new secondary metabolites of halotolerant fungi under high salt stress, and includes the following three parts:
1. Screening for the halotolerant talented strains.
From salt sediments and plants of mangrove forest in Hainan and Guangxi provinces,133 strains of halotolerant fungi have been isolated. The EtOAc ex tracts of these fungi cultured in 10% NaCl were evalassesed with the combinat ory method based on chemical and bioactive screening. Three of them were co nfirmed as halotolerant talented strains with cytotoxicity or antibiotic activities.
2. Study on secondary metabolites of four halotolerant talented strains und er high salt stress
Through the research of effect of different conditions, optimization of ferm entation conditions under high salt stress were determined. Four strains were fe rmented separately, then the whole broths were extracted with EtOAc in order to get active extracts. These extracts would be subjected to extensive silica gel column chromatography, Sephadex LH-20 and HPLC purifications. After proce ssing,78 compounds were isolated from these four halotolerant talented strains under salt stress. And 72 compound structures were identified by means of s pectroscopic analysis (such as UV, IR, NMR, MS, X-Ray, etc) and chemical methods. Among them,23 compounds were new types, including seven new p yrazinamide and linearity tetrapeptide (3-9) obtained from Aspergillus ochraceus P-Z cultured in a nutrient-limited medium containing 10% salts, eight new un saturated fatty acids and esters (12-19) from Cladosporium cladosporioides PXP -49 cultured in a nutrient-suffient medium containing 10% salts, five new cereb rosides with odd numbered carbon atom fatty acid (30-34) and two 2-pyridone alkaloids (35,36) from Penicillium chrysogenum PXP-55 cultured in a nutrien t-suffient medium containing 10% salts, and one pyridine alkaloids (44) from Wallemia sebi PXP-89 cultured in a actinomycete medium containing 10% salts. The known compounds are involved in phenolic compounds, sterols, macrocyc lic lactones, furan derivatives, and diketopiperazines. Compounds 4,8,9,31 an d 44 showed antibiotic activities against E. aerogenes with MIC values being 4 0,20.1,18.9,1.72 and 76.7μM, respectively. Compound 8 displayed antibiotic activity against S. aureus with MIC value 98μM.
3. Preliminary evaluation of halide salt effects on chemical diversity of sec ondary metabolites from halotolerant strains
To further research the halide salt effects on chemical diversity of seconda ry metabolites of halotolerant strains, the secondary metabolites of 6 halotolera nt strains under different culture conditions containing different halide salts at different concentration were studied by comparing their production, TLC, HPLC and bioactivities. The strain P-Z was found that it produced pyrazinamide dim ers (8,9) cultured in a hypersaline medium. In addition, it was established tha t different halide salts would affect the secondary metabolites of halotolerant st rains.
In summary, new compounds with bioactivity can be obtained from secon dary metabolites of halotolerant strains. Above studies provided a good exampl e for obtaining structurally new and bioactive compounds from halotolerant stra ins.
本论文从采自海南文昌清澜红树林保护区和广西山口红树林保护区的红树植物的叶和根部样品中获得3株耐盐天才真菌,从来源于海南临高附近海域的蕾二岐灯芯柳珊瑚的筛选到1株耐盐天才真菌；对这4株菌在盐胁迫条件下产生的次生代谢产物进行了系统研究,并就盐胁迫对耐盐天才真菌次生代谢产物化学多样性的影响做了探讨。
研究内容主要包括以下3个方面：
1.耐盐天才真菌的筛选。从来源于红树林高盐环境的样品中分离纯化获得133株耐盐真菌。以P388肿瘤细胞增殖抑制、抑菌试验作为生物活性筛选模型,TLC薄层色谱和HPLC指纹图谱作为化学筛选模型,采用生物活性和化学评价相结合的集成筛选模式,最终获得3株耐盐天才真菌。从来源于海南临高附近海域的蕾二岐灯芯柳珊瑚的筛选到1株耐盐天才真菌。
2.盐胁迫诱导下的4株耐盐天才真菌次生代谢产物的研究。对耐盐天才真菌进行发酵条件摸索,如培养基、发酵天数、盐度等,选择最佳培养条件进行大发酵,获得发酵浸膏。通过薄层色谱、硅胶柱色谱、Sephadex LH-20柱色谱、反相高效液相色谱等分离方法,从盐胁迫诱导的4株耐盐天才真菌次生代谢产物中,共分离得到78个单体化合物；应用波谱解析(UV, IR, NMR, MS, X-Ray等)和化学方法鉴定了72个单体化合物的化学结构。其中新化合物23个：从耐盐真菌赭曲霉Aspergillus ochraceus P-Z高盐条件代谢产物中获得了7个新的毗嗪酰胺类生物碱和线性四肽(3-9)；从枝孢样枝孢霉霉Cladosporium cladosporioides PXP-49高盐条件代谢产物中得到8个新的不饱和脂肪酸(酯)类化合物(12-19)；从产黄青霉Penicillium chrysogenum PXP-55高盐条件代谢产物中得到5个新的神经鞘胺醇糖苷类化合物(30-34)和2个新的2-吡啶酮类生物碱(35,36)；从耐盐真菌Wallemia sebi PXP-89高盐条件代谢产物中得到1个新的吡啶生物碱(44)。已知化合物的结构类型涉及苯的衍生物、脂肪酸类化合物、大环内酯类、甾体类化合物、呋哺衍生物和环二肽类化合物等。运用体外生物活性筛选模型,评价了新化合物的肿瘤细胞增殖抑制活性和抑菌活性。抑菌活性结果表明：吡嗪酰胺类和线性四肽类化合物4、8和9,神经鞘胺醇糖苷类化合物31,毗啶衍生物44对产气杆菌均具有抑制作用,MIC分别为40、20.1、18.9、1.72和76.7,μM；化合物8对金黄色葡萄球菌具有抑制作用(MIC,98μM),且这些化合物均为含氮化合物。
3.初步评价了卤盐胁迫对耐盐真菌次生代谢产物化学多样性的影响。使用对代谢产量、TLC、HPLC指纹图谱及生物活性作比较等方法,对高盐胁迫条件下6株耐盐真菌次生代谢产物的特点做了分析,利用该方法得到了一株在高盐条件下产生亮氨酸途径合成的线性四肽(8,9)的耐盐真菌(P-Z),证实了微生物的次生代谢存在卤盐效应。
综上所述,通过对耐盐天才真菌在高盐胁迫条件下次生代谢产物的系统研究,证实了盐胁迫能够增加耐盐微生物的化学多样性,产生新的活性含氮化合物,并为海洋药用微生物资源的开发提供了重要的参考。
Halotolerant microbe is one of extreme microorganism which can survive in high salt environment. Because of its specificity of living environment, halotolerant microbe may have unique secondary metabolic pathways and produce the unique secondary metabolites. Halotolerant microbe is an important class of resources for natural products. By integrated biological and chemical screening methods, talented strains with potential to produce chemically diverse secondary metabolites could be easily discovered. Further, the lead compounds with antitumor and antibiotic activity might be found from microbial secondary metabolites through optimization of the culture condition under high salt stress.
This dissertation focuses on the new secondary metabolites of halotolerant fungi under high salt stress, and includes the following three parts:
1. Screening for the halotolerant talented strains.
From salt sediments and plants of mangrove forest in Hainan and Guangxi provinces,133 strains of halotolerant fungi have been isolated. The EtOAc ex tracts of these fungi cultured in 10% NaCl were evalassesed with the combinat ory method based on chemical and bioactive screening. Three of them were co nfirmed as halotolerant talented strains with cytotoxicity or antibiotic activities.
2. Study on secondary metabolites of four halotolerant talented strains und er high salt stress
Through the research of effect of different conditions, optimization of ferm entation conditions under high salt stress were determined. Four strains were fe rmented separately, then the whole broths were extracted with EtOAc in order to get active extracts. These extracts would be subjected to extensive silica gel column chromatography, Sephadex LH-20 and HPLC purifications. After proce ssing,78 compounds were isolated from these four halotolerant talented strains under salt stress. And 72 compound structures were identified by means of s pectroscopic analysis (such as UV, IR, NMR, MS, X-Ray, etc) and chemical methods. Among them,23 compounds were new types, including seven new p yrazinamide and linearity tetrapeptide (3-9) obtained from Aspergillus ochraceus P-Z cultured in a nutrient-limited medium containing 10% salts, eight new un saturated fatty acids and esters (12-19) from Cladosporium cladosporioides PXP -49 cultured in a nutrient-suffient medium containing 10% salts, five new cereb rosides with odd numbered carbon atom fatty acid (30-34) and two 2-pyridone alkaloids (35,36) from Penicillium chrysogenum PXP-55 cultured in a nutrien t-suffient medium containing 10% salts, and one pyridine alkaloids (44) from Wallemia sebi PXP-89 cultured in a actinomycete medium containing 10% salts. The known compounds are involved in phenolic compounds, sterols, macrocyc lic lactones, furan derivatives, and diketopiperazines. Compounds 4,8,9,31 an d 44 showed antibiotic activities against E. aerogenes with MIC values being 4 0,20.1,18.9,1.72 and 76.7μM, respectively. Compound 8 displayed antibiotic activity against S. aureus with MIC value 98μM.
3. Preliminary evaluation of halide salt effects on chemical diversity of sec ondary metabolites from halotolerant strains
To further research the halide salt effects on chemical diversity of seconda ry metabolites of halotolerant strains, the secondary metabolites of 6 halotolera nt strains under different culture conditions containing different halide salts at different concentration were studied by comparing their production, TLC, HPLC and bioactivities. The strain P-Z was found that it produced pyrazinamide dim ers (8,9) cultured in a hypersaline medium. In addition, it was established tha t different halide salts would affect the secondary metabolites of halotolerant st rains.
In summary, new compounds with bioactivity can be obtained from secon dary metabolites of halotolerant strains. Above studies provided a good exampl e for obtaining structurally new and bioactive compounds from halotolerant stra ins.
引文
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