【医学ppt课件】antibiotics 抗菌素

Antibiotics,Antibiotics are microbial metabilites or synthetic analogs inspired by them that,in small doses, inhibit the growth and survival of microorganism. In clinic the antibiotics are used to be antibacterial mainly,but, in recent year, they can also be used for anti-cancer,anti-viral ,enzyme-inhibitors, and receptor-antagonist.,Classification (According their structures)：,1.Beta-Lactam antibiotics ( 内酰胺类) 2.Tetracylines antibiotics (四环素类) 3.Aminoglycoside antibiotics (氨基糖甙类) 4.Macrolides antibiotics (大环内酯类) 5. Others,Classification (According to their mechanism of actions,Inhibit the biosynthesis of bacterial cell walls ( Lactam) React with cell membrances (Polymycin) Disturber with the biosynthesis of protein (Aminoglycosides) Inhibit the replication and transcription of nucleonic acid (Nalicixic acid),1.* Lactam Antibiotics,*The group of antibiotics known as the -lactams include penicillins, cephalosporins, monobactams and the carbapenems.,These all share a common -lactam ring. The ring is very strained and the bond between the carbonyl and the nitrogen in the -lactam ring is very labile and hence makes the molecule reactive. The R-group substitute of the penicillin nucleus can be changed to give the molecule different antibacterial properties. The two naturally occurring penicillins from Penicillium notatum are Penicillin G, Benzyl penicillin, R = C6H6 and Penicillin V, Phenoxymethyl penicillin, R = CH2O(C6H6),The -lactam structure is derived from two covalently bonded amino acid residues; cysteine and valine. This forms via a tripeptide intermediate where the third amino acid is replaced by the variable R-group.,Mechanism of Action,D-Alanyl-D-Alanin,Penicillins,The peptidoglycan cell wall is a branched polymer made of alternating NAG -D-N-acetylglycosamine,乙酰葡糖胺 and NAM -D-N-acetylmuramic acid，乙酰壁氨酸 residues. Polypeptide chains are attached to the NAM residues and these vary depending on the strain of bacteria. The mechanism for cross-linkage is shown below. It is the terminal D-alanyl-D-alanine residues of the polypeptide chain off of the NAM residues that binds to the transpeptidase which cross-links that chain with the adjacent peptidoglycan strand. Penicillin binds at the active site of the transpeptidase enzyme that cross-links the peptidoglycan strands. It does this by mimicking the D-alanyl-D-alanine residues that would normally bind to this site.,The labile -lactam ring in penicillin reacts with a serine residue in the transpeptidase as shown below. This reaction is irreversible and so the growth of the bacterial cell wall is inhibited. The resulting complex is stable to water and remains attached to the polypeptide chain. The peptidoglycan transpeptidase is not needed in animals as their cells do not have cell walls. Therefore, the penicillin can safely disrupt the bacterial cell wall biosynthesis without harming existing cells in the body.,Penicllin-binding poteins,PBPs,Penicillin G and V are only active against Gram Positive bacterial cells, which have an exposed layer of peptidoglycan around the outside of the cell wall, as shown above. Gram Negative bacteria have a more complicated composition, which Penicillin G and V can not destroy,Penicliins Nature Penicillin (Fermentation-Derived Penicillins),Fleming found that it was effective against many Gram positive bacteria in laboratory conditions, and he even used locally applied, crude preparations of this substance, from culture filtrates, to control eye infections. However, he could not purify this compound because of its instability, and it was not until the period of the Second World War (1939-1945) that two other British scientists, Florey and Chain, working in the USA, managed to produce the antibiotic on an industrial scale for widespread use. In recognition for his contribution, Alexander Fleming was knighted in 1944. With Chain and Florey he was awarded the Nobel Prize in 1945. “One sometimes finds what one is not looking for.“,Because of its cheapness, efficacy, and remarkable lack of toxicity (except for acutely allergic patients). Peniciline G remains a remarkably useful agent for treatment of disease caused by susceptible microorganisms. It is the drug of choice for more infections than any other antibiotics. “ Fist is best” The disadvantages of Fermentation-Derived Penicillins (Penicillin G) 1.Narrower in antibacterial spectrum, active for G-P only, poor active for G-N 2.Can not be oral administrated , just for injection. 3.allergic action 4.susceptible to acid and Penicillinase 5.produces Penicllins-resistant bacteria.,青霉胺,青霉醛,青霉二胺,青霉酸,Semi- Synthetic Penicillins,SAR of Penicillins,Acid-resistant penicillins,R=,Beta-Lactamse resistant Penicillins,R=,Both Acid-resistant and Beta-Lactamase-resistant Penicillins,Broad Spectrum Penicillins,研究广谱青霉素的构效关系发现： 改变药物的极性，使之易于透过细胞膜可以扩大抗菌谱。如含有芳环侧链，在羰基a一位上引人极性亲水性基团一NH2、COOH、一SO3H等基团，可扩大抗菌谱，基团的亲水性越强，对革兰氏阴性菌作用越强，对绿脓杆菌也有效，有利口服吸收，并能增强对青霉素结合蛋白酶和力。 在分子中适当的部位引入立体障碍的基团可以克服耐药性。可降低对钝化酶的结构适应性，引入杂环，如茶啶，呋喃等，可得到耐酶和耐酸的抗生素。在杂环邻位带有甲氧基，双氟其立体效应可保护Bata一内酶胺环不被Bata一内酰胺进攻而得到耐酶药物。,青霉素噻唑环上的羧基是基本活性基团，不能被取代，只能用前药原理进行酯化，可增加口服吸收和改善药物代谢动力学性质，延长作用时间。改善药代动力学的方法是调节脂水分配系数，制备前药，或改造代谢不稳定的部位。 6a一位引入甲氧基或甲酰胺基，可增加Bata一内酰胺环的稳定性而得到耐酶抗生素。,Broad Spectrum Penicillins,R1,R2,Drugs,Characteristics,H,H,Ampinicillin (氨苄西林),对流感杆菌,痢疾杆菌,大肠杆菌,伤寒杆菌等有效,Amoxicillin 阿莫西林,抗菌谱与氨苄西林相似,口服吸收好,血药浓度高,*The synthetic routes of semi-synthetic penicillins,6-Aminopeciliianic Aicd,6-APA,Penicillin G,Typical drugs 1* Benzylpenicillin (青霉素G，苄青霉素）,青霉素G由青霉菌发酵得到，临床上已经用了半个多世纪，主要用其钠盐、钾盐。其特点是抗菌作用强，用于各种球菌和革兰氏阳性菌引起的全身或局部的感染。 其缺点是化学性质不稳定，易水解，只能注射给药。,2.*Ampicilin Sodium(氨苄西林),第一个用于临床的广谱口服青霉素,适用于革兰氏阳性球菌、杆菌、厌氧菌等所引起的呼吸道、尿道、肠道等感染。,3.*Amoxicilin Sodium(阿莫西林，羟氨苄青霉素),口服青霉素,与氨苄西林具有相同的抗菌谱，口服吸收好，血药浓度高，除对革兰氏阳性有较高活性外，对淋球菌、流感杆菌、百日咳杆菌、大肠杆菌等也有较强作用，但使用后易产生耐药性，临床上主要用于泌尿系统、呼吸系统、胆道等感染。,Cephalosporin (头孢菌素）,Decomposition of Cephalosporins in vivo,Decomposed by enzyme in vivo,(Inactive),(Inactive),The decoration of Cephalosporin,I: Relating with the antibacterial spectrum. II:Substituted with OCH3 will stability for Bata-Lactamase III: S atom is essential for activity. IV: Relating with the antibacterial activity and bioavailibility.,Semi-synthetic Cephalosprins,1.introducing lipophilic groups in 7-position( aromatic or heterocyclic rings ),R1,R2,2. introducing hydrophilic groups in position of 7-aimde group(-SO3H,-NH2,-COOH) will increase the antibacterial spectrum. Changing the 3-position to CH3,-Cl will improve the bioavailibility and increase antibacterial activity.,R1,R2,X,3.Introducing 2-amino-4-thiazol rings to the 7-position will increase the stabilities for Bata-Lactamase and expend the antibacterial spectrum.,R1 R2,4.esterification of 2-position COOH will improve the bioavailibility and obtained some good prodrugs.,R2 R1,5.quaternary ammonium salts are introduced to the 3-position,R,Synthetic Methods of Semi-Cephalosprins,*The preparation of 7-aminocephalospranic Acid (7-ACA),Method 1,Method 2,*The preparation of 7-amino-3-deacetoxycephalosporanic acid (7-ADCA),*Typical drugs,*1.Cefalixin(头孢立新,头孢氨苄,先锋IV号) 国家基本药物,7-(aminophenylacetyl)amino-3-methyl-8-oxo-5-thia-azabicyclo 4.2.0oct-2-ene-2-carboxylic acid monohydrate,半合成第一代头孢菌素,可口服,用于呼吸道,扁桃体,咽炎,尿路感染等,Synthetic route,*2.Cefaclor(头孢克洛,头孢氯氨苄、再克 ）国家基本药物,本品为半合成的第二代头孢菌素，抗菌谱及抗菌活性与头孢唑啉相似。对肺炎球菌、化脓性链球菌、葡萄球菌、奇异变形杆菌、大肠杆菌和肺炎杆菌、流感嗜血杆菌、淋病双球菌及厌氧菌等有良好抗菌活性。对产酶金葡菌、A型溶血性链球菌、草绿色链球菌和表皮葡萄球菌的活性与头孢羟氨苄相似。对奇异变形杆菌的活性也较强。 用于呼吸系统感染如肺炎、咽炎、扁桃体炎，尿路感染如肾于肾炎、膀胱炎，皮肤软组织感染等。 胃肠道反应，亦有变态反应如皮疹、荨麻疹及偶有转氨酶升高等。,*3.Cefotaxime Sodium(头孢噻肟钠,HR-756,凯福隆、凯福欣) 国家基本药物,(6R,7R)-3-(Acetyoxy)methyl-7-(amino-4-thiazolyl)-(methoxyimino) acetylamino-8-oxo-5-thia-1-azabicyclo 4.2.0oct-2-ene-2-carboxylic acid sodium 本品为第三代半合成头孢菌素，对革兰阴性菌的作用更强，抗菌谱包括嗜血性流感杆菌、大肠杆菌、沙门杆菌克雷白产气杆菌属及奇异变形杆菌、奈瑟菌属、葡萄球菌、肺炎球菌、链球菌等。 用于敏感菌引起的感染脑膜炎、呼吸系统感染、泌尿系统、软组织感染、菌血症等。,Synthetic route,*4.Cefoperazone(头孢哌酮,先锋必、泰福欣)国家基本药物,为第三代头孢菌素，对大肠埃希菌、克雷伯菌属、变形杆菌属、伤寒沙门菌、志贺菌属、枸橼酸杆菌属等肠杆菌科细菌和铜绿假单胞菌有良好抗菌作用，对产气肠杆菌、阴沟肠杆菌、鼠伤寒杆菌和不动杆菌属等的作用较差。流感杆菌、淋病奈瑟菌和脑膜炎奈瑟菌对本品高度敏感。 用于敏感菌引起的呼吸系统、泌尿系统、肝胆系统、皮肤及软组织、骨和关节、腹腔内感染和菌血症等。 副反应主要是斑丘疹、荨麻疹、药物热等，偶有血清转氨酶和碱性磷酸酶短暂升高，胃肠道反应有稀便、腹泻等、肠道菌群失调等。,Non-typical Bata-Lactam antibiotics and inhibitors of Bata-lactamase,The Carbapenem ,Monobactam, are belong to Non-typical Bata-Lactam antibiotics .,Bata-lactamase is produced by bacteria, which catalyse the hydrolysis of -lactams. There are about fifty different known types. The production of -lactamases by bacterial cells is the most important contributing factor to the development of penicillin-resistant strains of bacteria.,Carbapenem,Monobactam,Oxolactam,Inhibitors of Bata-lactamase,Penicillanic Acid Sulfone,*Subactam(舒巴坦,青霉烷砜),(2S,5R)-3,3-Dimethyl-7-oxo-4-thia-1-bicyclo3.2.0heptane-2-carboxylic acid