截短侧耳素—磺胺类拼合物的急性毒性及药效学研究

发布时间：2018-08-23 14:08

【摘要】：近年来,随着我国畜牧养殖业的高速发展,各种动物疾病特别是感染性疾病越来越多。抗生素作为养殖业中防治感染性疾病的主要手段,使用量也逐年递增,致使细菌耐药现象日益严重,尤其是耐甲氧西林金黄色葡萄球菌(MRSA)、耐青霉素肺炎链球菌(PRSP)、多重耐药铜绿假单胞菌(MDRPA)及耐万古霉素肠球菌(VRE)等耐药菌的出现,给人类的健康带来了严重威胁。研究对耐药菌有效的新型抗生素已迫在眉睫。当前,利用拼合原理合成新化合物的方法受到很多研究机构和药物公司的青睐。具有独特抗菌机制的截短侧耳素类抗生素很少与传统的抗生素发生交叉耐药,将其与已知抗生素或其药效基团拼合在一起,有望筛选出对耐药菌有效的新型化合物。为此,本课题组借鉴药物拼合原理,设计合成出46个新型截短侧耳素-磺胺类拼合物,筛选出6个有较好抗菌活性的拼合物。本文选择其中代表性的拼合物(A1、A3),研究它们的毒性及体内药效,为进一步阐述该类拼合物在动物体内的作用规律提供依据。毒性试验参考国标GB15193.3-2003的原理和方法,结果表明,拼合物A1、A3对小鼠经口急性毒性LD50为2296.1 mg/kg、1692.5 mg/kg,按照毒性分级均属于低毒物质。通过小鼠大腿和腹部皮下注射金黄色葡萄球菌ATCC29213,建立两种感染模型。以沃尼妙林为对照药物,口服给药,研究拼合物A3对两种疾病模型的治疗效果。结果表明,拼合物A3高、中、低剂量(507 mg/kg、338 mg/kg、169mg/kg)对小鼠大腿感染金葡后24h的大腿肌肉活菌数为:(7.01±0.32)×106 CFU/g,(2.32±0.12)×107 CFU/g,(9.9±0.43)×107 CFU/g,与空白对照组相比,差异极显著(P0.01),与沃尼妙林相当。A3高、中低剂量组对皮下感染化脓疾病的治愈率为88.89%、77.78%、50%,给药前后化脓面积平均分别减少2.08 cm2、1.59 cm2、1.42 cm2。沃尼妙林高、中低剂量组在给药前后化脓面积平均分别减少1.42 cm2、0.69 cm2、0.49 cm2,而对照组化脓面积平均增加了0.36 cm2。结果表明A3对于皮下化脓疾病的治疗效果良好,有较好的应用开发前景,为进一步研究该类化合物奠定了基础。
[Abstract]:In recent years, with the rapid development of animal husbandry in China, there are more and more animal diseases, especially infectious diseases. As the main means of preventing and curing infectious diseases in aquaculture, the use of antibiotics is increasing year by year, which results in the phenomenon of bacterial drug resistance becoming more and more serious. Especially the emergence of methicillin-resistant Staphylococcus aureus (MRSA), penicillin resistant Streptococcus pneumoniae (PRSP), multidrug resistant Pseudomonas aeruginosa (MDRPA) and vancomycin resistant Enterococcus (VRE) has brought a serious threat to human health. It is urgent to study new antibiotics that are effective against resistant bacteria. At present, the method of synthesizing new compounds based on splicing principle is favored by many research institutions and drug companies. Truncated Pleurotus antibiotics with unique antimicrobial mechanism rarely cross resistant with traditional antibiotics. Combining them with known antibiotics or their active groups, it is expected to screen new compounds that are effective against drug-resistant bacteria. For this reason, we designed and synthesized 46 new truncated Pleurogenin-sulfanilamides based on the principle of drug mosaic, and screened out 6 compounds with better antimicrobial activity. In this paper, the representative conjugate (A1A3) was selected to study their toxicity and in vivo pharmacodynamics, and to provide the basis for the further elaboration of the law of action of A1A3 in animals. The toxicity test referred to the principle and method of national standard GB15193.3-2003. The results showed that the acute toxicity of A1A3 to mice was 2296.1 mg / kg 路kg ~ (-1) 路kg ~ (-1) mg 路kg ~ (-1) 路min ~ (-1) mg / kg. Two infection models were established by subcutaneous injection of Staphylococcus aureus ATCC 29213 into the thigh and abdomen of mice. The therapeutic effect of A _ 3 on two disease models was studied. The results showed that the number of viable bacteria in the thigh muscle of mice infected with A3 was (7.01 卤0.32) 脳 106CFU / g, (2.32 卤0.12) 脳 107CFU / g, (9.9 卤0.43) 脳 107CFU / g (P0.01), which was significantly higher than that of control group (P0.01), compared with the control group (P0.01), and the number of viable bacteria in thigh muscle was (7.01 卤0.32) 脳 106CFU / g, (9.9 卤0.43) 脳 107CFU / g compared with control group (P0.01), and the number of viable bacteria in thigh muscle of mice was (7.01 卤0.32) 脳 107CFU / g, (9.9 卤0.43) 脳 107 CFU / g. The cure rate of middle and low dose group for subcutaneous infection and suppuration was 88.89 and 77.780.The area of suppuration was reduced by 2.08 cm _ 2 to 1.59 cm _ 2 and 1.42 cm _ 2, respectively. The purulent area decreased by 1.42 cm ~ (2) (0.69 cm ~ (2) 0.49 cm ~ (2) in the high, middle and low dose groups, and increased by 0.36 cm ~ (2) in the control group. The results showed that A3 had a good therapeutic effect on subcutaneous pyogenic diseases and had a good prospect of application and development, which laid a foundation for further study of this kind of compounds.
【学位授予单位】：华南农业大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：S859.7

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