第八章抗生素

1、2009-11-20nshxocoohrconhx = -h or -och3nshxocooharconhx = -h or -och3nonsonoono青霉素penicillins头孢菌素cephalosporins碳青霉烯carbapenem青霉烯penem单环-内酰胺monobactam氧青霉烷oxypenamohn(ch3)2ohconh2oohoohhhoh四环素类x = -h or -och3nshxocooharconhx = -h or -och3nshxocoohrconh内酰胺类ooohoohoooohohoonoh大环内酯类oho2nhohhhnoclclhohoho

2、honhch3ooohoohnh2nnhhoohohnnh2nhh氨基糖甙类nshxocoohrconhx = -h or -och3nshxocooharconhx = -h or -och3nonsonoono青霉素penicillins头孢菌素cephalosporins碳青霉烯carbapenem青霉烯penem单环-内酰胺monobactam氧青霉烷oxypenam x = -h or -och3nshxocooharconhx = -h or -och3nshxocoohrconhx = -h or -och3nshxocooharconhx = -h or -och3nshxoc

3、oohrconhnsohnhhorhoohnsonhhorhaoohpenicillinscephalosporins右图为苄青霉素钾的单晶衍射三维立体结构图像oosnnoo nshhocoohnhhonshhocoohnhor-内酰胺环-lactam ring四氢噻唑环thiazolidine ring6-氨基青霉烷酸6-aminopenicillanic acid( 6-apa )nshhocoohnhorcysval酰胺侧链acyl side chainnshhocoohnhho1234567nshhocoohnhhohnscoohnhhooohnhohoohonhoo- co2+青霉酸

4、penicilloic acid青霉醛酸penaldic acid青霉醛penilloaldehydeh+ or hgcl2shcoohnohonscoohn+hhoohnshhocoohnhhonnhoohsh nh2ooh青霉二酸penillic acid青霉醛penilloaldehyde青霉胺penicillamine+h+h+.ph = 4oh-+青霉胺penicillamine青霉醛penilloaldehydehsh nh2oohnhooshhocoohnhhonshhocoohnhhohnoh-co2shcoohnhhohnhgcl2青霉酸penicilloic acid青霉噻

5、唑酸penilloic acidnshhocoohnhhonshhocoohnhhoglcnacglcnacmurnacd-alal-alad-glum-dapd-alad-alam-dapd-glul-alamurnacglcnacglcnacmurnacd-alal-alad-glum-dapd-alad-alam-dapd-glul-alamurnacmurnacmurnacmurnacmurnac = n-乙酰胞壁酸glcnac = n-乙酰葡萄糖胺m-dap = meso-二胺基庚二酸glcnacglcnacmurnacd-alam-dapd-glul-alad-alaglcnacd

6、-alal-alad-glum-dapd-alad-alam-dapd-glul-alamurnacmurnacmurnacmurnacmurnacglcnacmurnac 转肽酶l-alad-glum-dapd-alad-alanh2. 2 pg cooh . 4 h2oh2nono. pg cooh . h2o普鲁卡因青霉素procaine benzylpenicillinpg cooh = benzylpenicillin苄星西林bicillin nshhocoohnhhorohohoohnh2名称取代基（r）来源青霉素g（penicillin g）从penicillium发酵得到青霉素

7、x （penicillin x）从penicillium发酵得到青霉素k （penicillin k）从penicillium发酵得到青霉素v （penicillin v）加入合成前体进行发酵青霉素n （penicillin n）cephalo sporium发酵得到r . h2onshhocoonanhono. h2onshhocoonanhono. h2onshhocoonanhono. h2onshhocoonanhononshhocoohnhonoph 3.8 , cu+( rearrangement )nnooohnohhshonshhocoohnhornoclnoclclnoclf

8、r：奈夫西林氯唑西林双氯西林氟氯西林. 3h2onshhocoohnhoh nh2ho. 3h2onshhocoohnhoh nh2ho. 3h2onshhocoohnhoh nh2honshhocoohnhoh nh2honshhocoohnhoh nh2hohnsnonhohnsonhnohnh2hnsonohhohohocoohcoohcoohn四元环及五元环的骈合是活性必需的此二个甲基不是活性必需的变为硫代酸或酰胺可不失活，还原成醇失活羧基是保持活性的必需基团，简单酯化可失活，但有时也可做成前药三个手性中心是活性必需的甲基或甲氧基取代活性降低6位侧链是结构修饰的主要部位，能产生各式各样

9、的作用snhhohoohnhornshhocoohnhonshhocoohh2npenicillin acylasepenicillin g6-apanshhocoohh2nhohnh2oclrooroncnnshhocoohnhoh nh2honshhocoohnhorrcoohnshhocoohnhornshhocoohnhoh nh2hohoonaohnshhocoonanhoh nh2honshhocoohnhononshhocoonanhonoaconach3ohx = -h or -och3nshxocooharconhh nh3+nhhonhosoohooo-onhhonhoso

10、ohoo7-aminoadipic side chain7-aminocephalosporinic acid ( 7-aca )-lactamdihydrothiazine ringacetatenhhonhosoohoorcysvalh nh3ooh nh3+nhhonhosoohooo-onhhonhosoohrohhoo+ho-nhhonhosoohoornhhonhosoohoornhhonhosoohohrnhhonhosroo3-hydroxycephalosporin头孢菌素内酯环ceohalosporin lactonec-3羟基化合物. h2onhhonhosoohh nh

11、3. h2onhhonhosoohh nh3nshhocoohnhhonhhonhosoonaoononsh2n广谱广谱耐酶耐酶nhhonhosoonaoononsh2nnhhonhosoonaoononsh2nnhhonhosoonaoonnsh2nouv254nmcis-trans-作用作用nhhonhosoohr3nsh2nnonnnohosnnnns头孢曲松头孢甲肟h头孢唑肟h nh3+nhhonhosoohooo-osnohnhoohoachr若以氧原子或亚甲基取代，不降低活性而得到另一类型内酰胺抗生素被甲基、氯原子或含氮杂环取代，活性增强或改变体内药代动力学双键移位则无活性c-7应

12、为l-构型，而酰胺侧链为-构型，c-6、c-7的氢为-构型，绝对构型为6r，7rc-7为同向(syn-)肟型或较大的取代基侧链时，对-内酰胺酶有较大稳定性，c-7对向构(anyi-)型时则不耐酶r为苯基、环烯基、噻吩或含氮杂环时能增强活性，扩大抗菌谱。芳核-碳引入-so3na、-nh2、-oh、-cooh等极性基团时，同时改变c-3上的取代基，可改进口服吸收、分布，也可扩大抗菌谱四元环与六元环不在同一平面，在c-6-n-1处折合hnh3+nhhonhosoohooo-onhhonsoohooohhoonhhosoohooh2nnhhonhosoohoosnhhonhosoohsn+nhhonh

13、osoohooononhhonhosoohoosnoh2nsoclsoclnh2nonooocln7-aca头孢噻吩cefalotin头孢噻啶cefaloridine头孢呋辛cefuroxime头孢噻肟cefotaximenaocl( )3耐药的金萄菌耐药的金萄菌医生的噩梦医生的噩梦noohoohoh发现发现noohoohoh属于不可逆性竞争型属于不可逆性竞争型-内酰胺酶抑制剂，与酶牢固结合内酰胺酶抑制剂，与酶牢固结合后使酶失活，作用强；后使酶失活，作用强；不仅作用于金葡菌的不仅作用于金葡菌的-内酰胺酶，对革兰氏阴性菌的内酰胺酶，对革兰氏阴性菌的-内酰胺酶也有作用；内酰胺酶也有作用；n克拉维酸

14、单独应用无效。通过与克拉维酸单独应用无效。通过与-内酰胺酶牢固地结合使酶不内酰胺酶牢固地结合使酶不可逆地失活，保护不耐酶的青霉家或头孢菌素类抗生素免遭破可逆地失活，保护不耐酶的青霉家或头孢菌素类抗生素免遭破坏，从而使后者更多地进入作用部位。坏，从而使后者更多地进入作用部位。n与青霉素类、头孢菌素类合用极大地提高了抗茵活性，可使其与青霉素类、头孢菌素类合用极大地提高了抗茵活性，可使其最低抑菌浓度最低抑菌浓度(mic)明显下降，药物可增效几倍至十几倍，使耐明显下降，药物可增效几倍至十几倍，使耐药菌株恢复其敏感性。药菌株恢复其敏感性。n口服给药对大肠杆菌、各种变形杆菌、炎杆菌、流感杆菌、肺口服给药对

15、大肠杆菌、各种变形杆菌、炎杆菌、流感杆菌、肺炎球菌等所致的尿道及呼吸道感染有良好的疗效。炎球菌等所致的尿道及呼吸道感染有良好的疗效。nshocoohoo舒巴坦为不可逆的竞争性-内酰胺酶抑制剂 snhooohoosnhhonhoooosnhoooohnh2注射用注射用舒巴坦舒巴坦-氨苄西林氨苄西林0.75g(含舒巴坦含舒巴坦 0.25g+氨苄西林氨苄西林 0.5g)nshocoohoonnnsnnohhhnonohooso oohnh2发现发现-诺卡霉素诺卡霉素snnohhhnonohooso oohnh2ohn(ch3)2ohconh2oohoohhhohohoohnoconh2ohohohh

16、h+nohconh2ohohhhohooh+- h2o- h+ohnohconh2ohohhhohoooh2+nohconh2ohohhhohoonohconh2ohhohohooohnohconh2oohoohhhohohohconh2ohohoohhhohh+nohconh2ohohoohhhohnoohconh2oohoohhhohnoh4-epitetracyclineoh-ohnohconh2ohohhhohooo-nohconh2ohohhohoonohconh2ohohoooohnohconh2o-ohohooohnohconh2o-oohohohoohnohconh2oohoo

17、hhhohmn+ohnohconh2oooohhhohmn+主要学习内容hnnhh2nhohoohhnnhnh2ohh2nhohoohnh2hnhohoohhnoh链霉胺streptamine2-链霉胺2-deoxystreptamine放线菌胺spectinamineohohohonhch3ooohoohnh2nnhhoohohnnh2nhhoh2nhoohoohohor2oohr1honhr3h2nkanamycin a r1 = -nh2 r2 = -oh r3 = -hkanamycin b r1 = -nh2 r2 = -nh2 r3 = -hkanamycin c r1 = -oh

18、 r2 = -nh2 r3 = -hamikacin r1 = -nh2 r2 = -oh r3 =nh2oohnhnh2nh2nhgentamicin c1 r = gentamicin c1a r = gentamicin c2 r = sagamicin r = ohoohh2noonh2h2nohohnrooohoohoooohohoonohoo12345678910111213hoonhoohoohooch3ohch3ohch3ohch3ch2ch2ch3ch3hoho13c酸内酯氨基去氧糖红霉糖ooohoohoooohohoonohooohoooohohoonohoooohoooo

19、hoonoohoooohoonooohohoooh+1. h+2. - h2o脱水物8,9-anhydroerythromycin a -6,9-hemiketal螺旋酮anhydroerythromycin a -6,9-9,12-spiroketal克拉定糖cladinoseooohoohoooohoroonoh红霉素碳酸乙酯erythromycin ethylcarbonate r = -cooch2ch3红霉素硬脂酸酯erythromycin stearate r = -co(ch2)16ch3琥乙红霉素erythromycin ethylsuccinate r = -co(ch2)2

20、ococh2ch3依托红霉素erythromycin estolate r = -cooch2ch3, c12h25so3honohoohoooohohoonooooohoohoooohohoonohn阿齐霉素azithromycindirithromycinerythromycin oxime罗红霉素roxithromycin甲基化还原beckmannrearraangementonohoohoooohohoonooooohoohoooohohoonohnoohoohoooohohoonohhnoohoohoooohohoonohhnoonohoohoooohohoonohoooooohoo

21、hoooohohoonohonohoohoooohohoonohohoohoohoooohohoonohofoooohoooohohoonoho氟红霉素flunithromycin克拉霉素clarithromycinoohoooohoonononnn自学oho2nhohhhnoclclh氯霉素甲砜霉素oho2nhohhhnoclclhoho2nhohhhnoclclhoho2nhohhhnoclclhoho2nhohhhnoclclh1r, 2r (-) 1s, 2s (+) 1s, 2r (+) 1r, 2s (+)d-(-)-threo l-(+)-threo d-(+)-erythro l-(-)-erythrono2c1c2ch2ohhhonhcochcl2hno2c1c2ch2ohohhhcl2chcohnno2c1c2ch2ohohhnhcochcl2hno2c1c2ch2ohhhohcl2chcohno2nohhhohhnoclclho2nohhhohhnoohohho2nohhnh2hoho2noh+p-nit