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1、抗生素的作用机制 Mechanism of antibiotic,1.干扰细菌细胞壁合成 2. 损伤细菌细胞膜 3. 抑制细菌蛋白质合成 4. 抑制细菌核酸合成 5. 增强吞噬细胞的功能 1. To interfere with the synthesis of bacterial cell wall 2. To damage the cell membrane of bacteria 3. To inhibit protein synthesis of bacteria 4. To inhibit nucleic acid synthesis of bacteria 5. To enhanc
2、e the function of phagocytes,To be classified according to chemical structure：,1，-内酰胺类,-lactams 2，四环类, tetracycline antibiotics 3，氨基糖苷类, Aminoglycoside antibiotics 4，大环内酯类, Macrolide antibiotics 5，其他类, other types,11.1-Lactam Antibiotics,1. Structural Characteristic and Mechanism of Action Classific
3、ation,The basic structure of-lactam antibiotics,青霉素类 头孢菌素类 碳青霉烯类,头霉素类 单环-内酰胺类,The characteristics of the chemical structure,-lactam ring: 四元-内酰胺环环通过N原子和邻近的第三碳原子与另一个五元环或六元环相稠合，青霉素的稠合环是氢化噻唑环，头孢菌素是氢化噻嗪环。 A carboxyl group: 与-内酰胺环稠合的环上都有一个羧基。 An amide side-chain: 内酰胺环羰基-为碳都有一个酰胺基侧链。,Stereochemistry: -内酰胺
4、环为一个平面结构。但两个稠合环不共平面，青霉素沿N1-C5轴折叠，头孢菌素沿N1-C6轴折叠. Polarimitry structure: 青霉素类抗生素的母核上有3个手性碳原子，8个旋光异构体中只有绝对构型为2S，5R，6R具有活性。头孢菌素类抗生素的母核上有2手性碳，4个旋光异构体，绝对构型是6R，7R。-内酰胺类抗菌活性不仅与母核的构型有关。而且还与酰胺基上取代基的手性碳原子有关，旋光异构体间的活性有很大的差异。,The mechanism of -lactam antibiotics,biosynthesis of cell wall,Resistance and mechanism
5、 of -lactam antibiotics,Penicillin antibiotics,Penicillin G Penicillin X Penicillin V,Penicillin F Dihydropenicillin F,Penicillin N Penicillin K,Benzylpenicillin,(2S，5R，6R)-3，3-二甲基-6-(2-苯乙酰氨基)-7-氧代-4-硫杂-1-氮杂双环3.2.0庚烷-2-甲酸,青霉素G(Penicillin G) (2S，5S，6R)-3，3-Dimethyl-6-(2-Benzylacetamido)-7-oxo-4-thia-
6、1-azabicyclo3.2.0 heptane-2-carboxylic acid。,Chemical properties and characteristics of Penicillin G,Acidic conditions:,Alkaline conditions:,Prodrugs of penicillin,苄星西林,Semi-synthetic penicillin,Shortcomings of Penicillin : non acid- resistent, non enzyme-resistent, narrow anti-bacterial spectrum an
7、d allergic reactions Semi-synthetic penicillins: Acid-resistant penicillin Enzyme-resistant penicillin Broad-spectrum penicillin Compounds of Penicillin and -lactamase inhibitor,Acid-resistant penicillin,天然青霉素中青霉素V可以口服，不易被胃酸破坏,说明具有耐酸性质，虽其抗菌活性低于青霉素G,但其耐酸的性质值得注视。它的结构与青霉素G的差别是6位酰胺基上是苯氧甲基，为吸电子基团，可降低羟基上的
8、电子密度，从而阻止了侧链羰基电子向-内酰胺环的转移，增加了对酸的稳定性，根据同系物原理设计合成了在酰胺基位引入O、N、X等电负性原子的衍生物。,azidocillin phenethicillin propicillin,Enzyme-resistant Penicillin,meticillin 萘夫西林,Oxacillin Series,美西林,匹美西林,Broad-spectrum penicillin,Penicillin N ampicillin amoxicillin,carbenicillin sulbenicillin,piperacillin,apalcillin,mezlo
9、cillin,ticarcillin 福米西林,pivalpicillin,Amoxicillin,(2S，5R，6R)-3，3-二甲基-6-(R)-(-)-2-氨基-2-(4-羟基苯基)乙酰氨基-7-氧代-4-硫杂-1-氮杂双环3.2.0庚烷-2-甲酸三水合物,又名羟氨苄青霉素 (2S， 5S， 6R)-3，3-Dimethyl-6-(R)-(-)-2-amino-2-(4-hydroxyphenyl)acetamido-7-oxo-4-thia-1-azabicyclo 3.2.0heptane-2-carboxylic acid trihydrate,Chemical stability
10、,各种糖类(葡萄糖和葡聚糖)和多元醇在碱性条件下均能加速其分解，发生分子内成环反应，生成2，5-吡嗪二酮。因此不宜采用葡萄糖溶液作为稀释剂,The structure-activity relationships of penicillins,The side-chain at 6 is important to the antimicrobial spectrum. To change its polarity, make it go through cell membrane easily can expand its antibacterial spectrum. An extra th
11、ree-dimensional obstacle group at the appropriate place will increase the resistance to passivation enzyme, can avoid the attack from -lactamase. It is possible to produce the enzyme-resistant antibiotics.,The carboxyl on thiazolidine ring is the essential activity group of penicillin: 被硫代酸或酰胺取代活性降低
12、，被还原为醇时失去抗菌活性。对其羧基可利用前药原理进行结构修饰，以增加口服吸收和改善药物代谢动力学性质。 The configuration of the three chiral carbons is essential for the activity, but the two methyls on the thiazole ring is not necessary to maintain the activity.,The semi-synthetic method of penicillin,6-氨基青霉烷酸,1. 酰氯法：,2. 酸酐法,3. method of DCC,4. En
13、zymatic solid-phase method To fix the catalytic enzyme in a certin place, make it to catalyze the direct condensation of side chains and 6-APA. The method is simple and high yield. The key issue is to ensure the catalytic activity of enzyme.,1.2 Cephalosporins,Natural cephalosporins Cephalosporin wa
14、s separated from cephalosporin (Cephalosporium), it was hydrogenated lactam ring of antibiotics thiazine ring, there were three natural cephalosporins : cephalosporin bacteria Su-C, N and P. 头孢菌素P抗菌活性中等，但耐药性强。头孢菌素N抗菌活性较低，而头孢菌素C的抗菌谱广、毒性较小。但由于抗菌活性与其半合成头孢菌素的活性无法比拟，所以在临床上几乎没有应用。,Stability of cephalospor
15、ins,The classification and its structural characteristics of semi-synthetic cephalosporin,First-generation cephalosporins,头孢唑林( Cefazolin) 头孢噻啶( Cefaloridine),头孢匹林 (Cephapirin) 头孢噻吩( Cefalothin) 头孢乙腈( Cefacetrile),First-generation cephalosporins was penicillin enzyme-resistant, but intolerance to -l
16、actamase:主要用于耐青霉素酶的金黄色葡萄球菌等敏感革兰阳性球菌和某些革兰阴性球菌的感染。,头孢氨苄 (Cefalexin) 头孢羟氨苄 (Cefadroxil) 头孢拉定( Cefradinel),Second-generation cephalosporins,头孢尼西 (Cefonicid) 头孢呋辛( Cefuroxime) 头孢丙烯( Cefprozil),头孢雷特( Ceforanide) 头孢替坦( Cefotatan) 氯碳头孢 (Loracarbef),Characteristics of second-generation cephalosporin,Second-g
17、eneration cephalosporins has not notable distinction with the first-generation cephalosporins in the chemical structure. It is stable to the majority of -lactamase and with broader antimicrobial spectrum, stronger activity to gram-negative bacteria than the first generation, but it is weaker to anti
18、-Gram-positive.,Third-generation cephalosporins,头孢噻肟(Cefotaxime) 头孢唑肟(Ceftizoxime),头孢曲松(Ceftriaxone) 头孢他啶(Ceftazidime),头孢哌酮(Cefoperazone) 头孢克肟(Cefixime),头孢噻腾(Ceftibuten) 头孢地尼(Cefdinir),头孢泊肟酯(Cefpodoxime proxetil),Third-generation cephalosporins has much broader antibacterial spectrum, with the stron
19、ger effect to gram-negative bacteria, but the weaker effect to Gram-positive bacteria than first generation, some drug has strong activity resistance toward Pseudomonas aeruginosa.,Characteristics of third-generation cephalosporin,Third-generation cephalosporin has obvious chemical structure charact
20、eristics in side chain. Mostly it has 2 - amino-thiazole-methoxyimino acetyl, the introduction of imino double bond lead to the cis isomer and tran-isomer. cis-isomer presents more stability to -lactamases than tran-isomer for the short distance to -lactam ring.,Fourth-generation cephalosporins,头孢匹罗
21、(Cefpirom) 头孢吡肟(Cefepime),头孢唑兰(Cefozopran) 头孢瑟利(Cefoselis),Characteristics of fourth-generation cephalosporin,There is side-chain of 2 - Aminothiazole-methoxyimino acetyl Quarter amine group at 3 and carboxyl form the inner salt.具有较低-内酰胺酶亲和性与诱导性，可通过革兰阴性菌外膜孔道迅速扩散到细菌周围并维持高浓度，对青霉素结合蛋白亲合力强。因此其抗菌活性更强，尤其是
22、对金黄色葡萄球菌等革兰阳性球菌，并且对-内酰胺酶尤其是超广谱质粒酶和染色体酶稳定，穿透力高。,Structural transformation of Cephalosporins,Amide substituent at 7 is essential to antibacterial spectrum, the structural modification at 7 can expand the antibacterial spectrum and enhance antibacterial activity. Methoxy substitutes the hydrogen atom a
23、t 7 can improve the stability of-lactam ring. S is replaced by O or C can improve the antibacterial activity. Substituent at 3 can not only improve antibacterial activity, but also affect pharmacokinetics.,SQR of Semi-synthetic cephalosporin, The introduction of lipophilic group at side chain of 7 s
24、uch as benzene, thiophene, heterocyclic ring with nitrogen, and the introduction of heterocyclic ring at 3 can expand the antibacterial spectrum, enhance the antibacterial activity.如第一代的头孢菌素的头孢噻吩、头孢噻啶、头孢唑林和头孢匹林。 The introduction of hydrophilic group at 7 -amide group such as -SO3H,-NH2,-COOH, can ex
25、pand anti-bacterial spectrum to pruduce broad-spectrum cephalosporins, 此类药物对绿脓杆菌的外壁有很高的渗透作用，此基团的引入既增加了口服吸收，也极大地改变抗菌活性对酶的稳定性。若同时用-CH3、- Cl或含氮杂环取代基替代3位上的取代基，除改进口服吸收外还可使其对革兰氏阴性菌和绿脓杆菌都有效。, 7- cis-methoxy imino -2 - thiazolyl ammonia can increase stability to -lactamase. And expand the antimicrobial spec
26、trum by reason of enhancing penetration to outer membrane of gram-negative bacteria. Oxime methoxy of side-chain at 7 changes into carboxy can avoid cross-allergy，如将头孢噻肟改造成头孢他啶，头孢克肟,口服后血药浓度高，持续时间长，具有良好的生物利用度。, Transformation at 3, such as acet-methoxy is replaced by-CH3 or -Cl, can enhance antimicro
27、bial activity, and improve absorption, distribution in vivo and the penetration through the cells of the pharmacokinetics.为了克服头孢菌素半衰期短，代谢不稳定，对-内酰胺酶缺乏稳定的缺点，除在7-氨基上引入不同的酰基外。在3-甲基上以硫代杂环取代乙酰氧基, 其硫代杂环的结构特征和理化性质，如环的大小、位置、杂原子的类型数目、芳香性和亲水性等均与其抗菌活性活性有关。用带有酸性功能基的杂环替代乙酰基，使蛋白结合力增强，在血浆中半衰期长，成为长效抗生素。, Carboxyl gr
28、oup at 2 is anti-bacterial activity group, can not be changed. Esters of prodrug can be made in order to improve the pharmacokinetics, prodrug esters improve the oral absorption and bioavailability. In the body the prodrug can be hydrolyzed quickly by non-specific esterase to give out the original d
29、rugs so can extend the acting time. For fourth-generation cephalosporins, positively charged quaternary ammonium group at 3 of drugs increased the penetration through the cell membrane and showed a low affinity to -lactamase. The introduction of methoxy of 7 produces cephamycin derivatives, the ster
30、eochemistry of methoxy can block the approaching of lactam to enzyme, so increase the stability to-lactamase and thus enhance the activity to anaerobic bacteria., Oxygen cephalosporin and carbon cephalosporin vinyl would be produced if S was replaced by bio-electronic body-O- and -CH2-, respectively
31、. 碳头孢烯由于立体位阻作用使药物耐-内酰胺酶，具有广谱、耐酶、长效的性质。-CH2-取代S原子后，增加了药物在体内的稳定性。,Synthetic of cephalosporin,亚硝酰氯法:,硅酯法:,青霉素扩环法：,Nonclassical Lactam Antibiotics and Lactamase Inhibitors,Carbapenem antibiotics,克拉维酸 Clavulanic Acid,Mechanism of clavulanic acid,舒巴坦 Sulbactam,Synthesis of sulbactam,Sulbactam derivatives,
32、舒它西林,他唑巴坦,Monocyclic -lactam,氨曲南 替吉莫南 卡芦莫南,11.3 Tetracycline Antibiotics,Naphthacene derivatives with (1,2,3,4,4 a, 5,5a,6,11,11a,12,12a) -odecahydronaphthacene,Tetracycline and its chemical properties,Tetracycline 6-甲基-4-(二甲氨基)-3,6,10,12,12a-五羟基-1,11-二氧代-1,4,4a,5,5a,6,11,12a-八氢-2-并四苯甲酰胺(6-Methyl-4-
33、(dimethylamino)-3,6,10,12,12a-pentahydroxy-1,11-dioxo-1,4, 4a,5,5a,6,11,12a- octahydro-2- naphthacenecarboxamide。,Tetracycline antibiotics has both the acid group of phenolic and enol hydroxyls and alkaline dimethylamino, so with the properties of acid and alkaline presenting three pKa values of 2.8
34、 3.4, 7.2 7.8, 9.1 9.7. Tetracyclines are relatively stable in solid state and dry condition, but may change color meeting sunlight. In acidic and alkaline conditions are not stable and prone to hydrolyze.,The chemical properties of tetracycline,Under acidic condition, tetracycline decline to the el
35、imination reaction of giving off H2O from the C-6 hydroxyl and C-5a hydrogen to generate the inactive orange Anhydrotetracycline. 由于C-6上的羟基与C-5a上的氢正好处于反式构型，在酸性条件下有利于发生消除反应。,In case of pH 2-6, dimethylamino at C-4 is prone to produce reversible epimerization to generate epimer: 某些阴离子如磷酸根、枸椽酸根、醋酸根离子的存
36、在，可加速这种异构化反应。4位差向异构化产物在酸性条件也还会进一步脱水生成脱水差向异构化产物。四环素类药物的脱水产物及差向异构体的抗菌活性均减弱或消失。差向异构体的活性不仅减弱，而且毒性为四环素的23倍，主要毒性为可引起Fanconi综合征，肾小管的在吸收功能受损，产生烦渴、蛋白尿、糖尿、氨基酸尿、低血钾、高尿酸血症和酸中度。四环素与其4-差向异构体在一定的条件下以动态平衡关系而互存。因此各国药典都对其含量进行不程度的控制。,Under alkaline condition, OH at C-6 change into oxygen anion and then attacks the C-1
37、1 lead to intramolecular nuclear reaction, by electron transfer, C ring rupture to generate inactive lactone isomer (isotetracycline),Reaction with metal ions: tetracycline antibiotics contain a few hydroxyl, enol hydroxyl and carbonyl, so under the near-neutral conditions react with a variety of me
38、tal ions to form insoluble chelates.与钙或镁离子形成不溶性的钙盐或镁盐，与铁离子形成红色络合物；与铝离子形成黄色络合物。,Semi-synthetic tetracycline antibiotics,Doxycycline hydrochloride,Synthesis of Doxycycline Hydrochloride,SAR, mechanism and drug resistance of tetracyclines antibiotics,SAR of tetracyclines: 1. Tetracycles in tetracycline
39、 is required for biological activity, substituents at position 1-4 in ring A is the basic pharmacophore for antibacterial activity, changing of it lead to the activity disappearing, only place for prodrug modification is on the amide groups. 2. one structure located at C11-C12a is essential for anti
40、bacterial activity.,3. Substituents on places 5-9 are not active groups, its transformation can change the antibacterial activity, chemical stability and pharmacokinetic properties of the drugs. 4. 6 carbon atom at place 6 substituted by sulfur can lead to the drugs with the antibacterial activity s
41、uperior to doxycycline, and long-lasting, broad spectrum, high concentration after oral taking.,2. Drug resistance and mechanisms Tetracyclines can inhibit the synthesis ribosomal protein of bacterial to inhibit the growth of bacteria, they are the broad-spectrum antibiotics. Tetracyclines-resistant
42、 bacteria has been found because of the long-term use of tetracycline.,11.4 Aminoglycoside Antibiotics,Aminoglycoside antibiotics arised from streptomyces, micromonospora and bacteria. The chemical structure of these antibiotics is usually composed of 1,3 - diamino inositol and some certain amino su
43、gars linked by glucoside bond.,These antibiotics are alkaline for its chemical structure characteristics, usually crystalline form of the sulfate or hydrochloride salt in clinical suage. Aminoglycoside antibiotics are polar compounds, high water-soluble but low fat-soluble, difficult to be absorbed
44、in the gastrointestinal tract by oral administration, the low rate of serum protein binding in case of injection. The vast majority did not metabolize in vivo and discharge as the original form. Toxic to the kidneys and also to eighth cranial nerve (ototoxicity), cause hearing loss, neuromuscular bl
45、ockers and allergic reactions.,Mechanism of aminoglycoside antibiotics,Inhibit biosynthesis of bacterial protein to kill the them.,Mechanism of drug resistance,To produce inactivating enzyme to change the structure of aminoglycosides leading to the loss of antibacterial activity, or by changing the
46、permeability of bacterial cell membrane lead to non-specific drug resistance. Aminoglycoside antibiotics usually have cross-resistance.,Streptomycin,Kanamycin and its Derivatives,Gentamicin and its Derivatives,11.5 Macrolide Antibiotics,Structural characteristic, physicochemical property、and mechani
47、sm of Macrolide Antibiotics 1. Structural characteristic Macrolide antibiotics produced by Streptomyces, a kind of alkalescence antibiotics, the molecular structure containing a lactone macrocycle formed by fourteen or 16 atoms and there is a alkaline glycoside formed by hydroxyl on lactone and amin
48、o-deoxy sugar or 6 - deoxy sugar.此类药物的碱性较弱，大约为pH8，游离的碱不溶水，其葡庚糖酸盐和乳糖酸盐的水溶解度较大，而其他盐如硬脂酸盐和十二烷硫酸盐的水溶度降低。,2. Physicochemical properties Generally macrolide antibiotics are alkaline compounds, colorless, soluble in organic solvents. Can change into salt with acids, the salt is soluble in water, chemically unstable in acidic conditions, the glycoside bond are susceptible to hydrolysis and when breakdown of the lactone r