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抗生素. 一、 History 1. 神農嚐百草,雲南白藥-- chemotherapy 2. Paul Ehrlich(a chemist) — 真 正使化學治療成為 一門科學的人。 Salvarsan a. 提出 selective toxicity idea b. 發現某些 dyes 與 tissue 有親和力,如果這些 dyes 又具有殺菌力豈不妙哉!可惜沒有進 一步發現。 3. 1935 年 Domagk 發現了磺胺劑 (sulfonamides) ,脫離

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slide1
抗生素

一、History

1. 神農嚐百草,雲南白藥--chemotherapy

2. Paul Ehrlich(a chemist)—真正使化學治療成為

一門科學的人。Salvarsan

a. 提出selective toxicity idea

b. 發現某些dyes 與tissue有親和力,如果這些

dyes又具有殺菌力豈不妙哉!可惜沒有進

一步發現。

3. 1935年Domagk發現了磺胺劑(sulfonamides),脫離

了dye的觀念,開始從organic compounds中找drug。

slide4
抗生素

4. Alexander-Fleming 1928-1929年間,發現在實驗室中的培養基(S. aureus),被Penicillium污染,周圍出現Clear zone—Penicilln。

5. 1940年,Florey and Chain將penicillin分離出來並在美國大量製造。

6. Streptomycin, Tetracycline, Chloramphenicol相繼被發現,不僅在Fungi,在Bacteria如Streptomyces亦可產生。

7. Fermentation

slide5
抗生素發展
  • 大量生產
  • 提高單位產量
  • Screening—某些微生物可產生多種抗生素,但比率不同,必須能篩選出我們所要的一種。
  • 淘汰—目前抗生素有4,000-5,000種,但市面上僅有100多種,不良的已經淘汰。
  • R&D
slide6
半合成抗生素
  • 某些活性差,產量少之抗生素,如cephalosporins, rifamycin等,可以用chemical modification的方法,將其structure稍加改變而獲得改善--轉弱為強(new antibiotics, eg. cephalosporin→cephaloridine; rifamycin→rifampicin
  • 以penicillin為例

a. b-lactam

b. thiazolidine

c. 6-APA (6-amino-penicillanic acid)

slide7

6

1

5

a

2

b

4

3

6-APA

semi synthetic penicillins
Semi-synthetic penicillins

Culture of Penicillium Chrysogenum

+ phenylacetic acid

Penicillin G (benzyl penicillin)

Remove side chain

6-Aminopenicillanic acid (6-APA)

ROCl

Semi-synthetic penicillins

e.g., Ampicillin—a-aminobenzyl P

Methicillin—dimethoxyphenyl P

slide9
半合成抗生素之優點
  • Extended spectrum—殺菌範圍增加了。

eg. Penicillin本來只能殺Gram(+),但改良後ampicillin可殺Gram (-)。

  • Resistance to certain bacteria

eg.methicillin可以抑制會產生penicillinase的細菌。

  • Easy to take

eg.penicillin G 多用於注射,若口服會被胃酸破壞。而penicillin V,cephalexin則可口服,較方便。

  • Improve pharmacokinetic properties

eg. Amoxicillin易進入blood中,血中濃度提高,增加殺菌能力。

  • Increase potency
american hospital formulary service 1996
抗生素分類(依照 American Hospital Formulary Service, 1996)
  • 胺基酸糖體類
  • 抗黴菌類
  • 頭孢子菌類
  • 青黴素、頭孢子菌類除外之b-丙醯胺抗生素類

eg. carbapenems, Meropenem, Aztreonam (monobactam)

  • 氯黴素類
  • 巨環類
  • 青黴素類
  • 四環素類
  • 其他抗生素類
how do antibiotics work
How do antibiotics work?
  • Work on cell wall—eg. Penicillin, cephalosporin, cycloserine, polypeptides (eg.bacitracin), vancomycin.

細胞壁的結構與合成

  • 細胞壁係由peptidoglycan(又稱mucopeptide or murein)形成之complex polymer;包括

polysaccharide & polypeptides二components.

  • polysaccharides=N-acetyglucosamine +

acetymuramic acid.

cycloserine
Cycloserine抑菌機制

L-Ala D-Ala

2 D-Ala D-alanyl-D-alanine

D-alanyl-D-alanine synthase

Ala racemase

cycloserine

how do antibiotics work16
How do antibiotics work?
  • Work on cell wall

Penicillin之結構與細胞壁合成時peptidoglycan strand 之D-alanyl-D-alanine相類似,因此,penicillin與合成時之酵素(transpeptidase)形成acyl enzyme intermediate,阻斷酵素的功能。亦就是說,阻礙了細胞壁合成過程中之alanine transpeptidation步驟。

b-lactam antibiotics 對G(+)和G(-)作用效果不同,主要是cell wall 的結構不同所致。

1. Peptidoglycan的量

2. Presence of receptors

3. Presence of lipids

4. Enzyme activity

how do antibiotics work17
How do antibiotics work?
  • Work on cell membrane

eg. Polymyxins (polymyxin B)—作用在phosphatidylethanolamine (G-)

eg. Polyenes (nystatin, amphotericin B)—作用在sterol (fungi)。

  • Inhibition of protein synthesis

DNA→RNA protein

Bacteria: 70S (50S + 30S)

Mammalian: 80S (60S + 40S)

ribosome

how do antibiotics work20
How do antibiotics work?
  • Inhibition of protein synthesis

為何antimicrobial drugs能抑制細菌蛋白質合成而不太影響哺乳類蛋白質合成?

  • Subunit 不同
  • Chemical composition不同
  • Functional specificities不同
how do antibiotics work21
How do antibiotics work?
  • Inhibition of protein synthesis

eg. Aminoglycosides: Streptomycin, kanamycin, neomycin, gentamicin, tobramycin, amikacin等。其抑菌機制可歸納如下:

a. 附於30S 上

b. 阻止peptide formation中之initiation步 驟。

c. mRNA帶來的信息被唸錯。

d. 將polysome拆散變成monosomes.

例如:有些細菌改變了ribosomes導致對streptomycin具有抗性。

how do antibiotics work22
How do antibiotics work?
  • Inhibition of protein synthesis

eg. Tetracyclines: Tetracycline, chlorotetracycline(金黴素), oxytetracycline(土黴素), doxycycline, minocycline等。基本上tetracyclines之作用機制為:

a. 附於30S 上

b. 阻礙aminoacyl-tRNA的anticodon binding.

大多數tetracycline resistance菌株係由於改變細胞膜的通透性、或改變抗生素所不活化的酵素所致。真核細胞的ribosome亦對tetracycline敏感,但是該抗生素不能穿過真核細胞的細胞膜,所以in vivo上不能抑制真核蛋白的合成。

how do antibiotics work23
How do antibiotics work?
  • Inhibition of protein synthesis

eg. Chloramphenicol:毒性較大,因為mitochondrial ribosomes are sensitive to the antibiotic.

作用機制:

a. 結合到50S ribosomal subunit.

b. specifically inhibits the peptidyl

transferase reaction.

how do antibiotics work24
How do antibiotics work?
  • Inhibition of protein synthesis

a. 結合到50S ribosomal subunit.

b. specifically inhibits the peptidyl

transferase reaction.

eg. Macrolides: erythromycin, leucomycin, oleandomycin.

eg. Lincomycin, clindamycin

how do antibiotics work25
How do antibiotics work?
  • Inhibition of nucleic acid synthesis

eg. actinomycin D:The mechanism of the inhibition of RNA synthesis is caused by the insertion (intercalation) of its phenoxazone ring between two G-C base pairs, with the side chains projecting into the major groove of the double helix, hydrogen bonded to guanine residues. RNA polymerase binding to DNA that contains actinomycin D is only slightly impaired, but RNA chain elongation in both eukaryotes and prokaryotes is blocked.

eg. mitomycin C:對DNA有特異的阻礙作用,可使DNA崩解。

eg. Rifampin:抑制細菌mRNA合成

how do antibiotics work26
How do antibiotics work?
  • Inhibition of purine and pyrimidine synthesis

eg.Azaserine:與L-Glutamic acid的化學結構相似。Inhibition is irreversible, with formation of a covalent bond between the inhibitor and an amino acid side chain at the catalytic site. The specific reactions inhibited are those catalyzed by glutamine PRPP aminotranferase and phosphoribosyl-N-formylglycinamidine synthase in the de novo purine pathway and carbamoyl phosphate synthase and CTP synthase in the pyrimidine pathway.

how do antibiotics work27
How do antibiotics work?
  • Affecting energy metabolism:抑制oxidative phosphorylation以阻礙能的代謝作用抑制細菌的生長。

eg. Antimycin, gramicidin S, oligomycin

oligomycin:act directly on the ATP-synthase that converts ADP and Pi to ATP.

antimycin A:加入antimycin A時,cytochrome B變為reduced state; cytochrome C 變為oxidized state

how do antibiotics work28
How do antibiotics work?
  • 抑制細菌之主要代謝物(metabolite):此metabolite為細菌代謝過程的必需物質。eg. Sulfa抑制PABA (para-aminobenzoic acid,對氨安息香酸)。
synergism and antagonism
Synergism and Antagonism
  • Synergism(協和性):某一種藥物能加強另一種藥物作用。

eg 1. clavulanic acid + amoxicillin 其中clavulanic acid 會抑制b-lactamase活性。amoxicillin抑制cell wall 的合成。若二者同時使用效果更佳。

eg 2.sulfonamide (5 parts) + trimethoprim (1 part) = co-trimoxazole 具有synergism 用於尿道感染之治療。

sulfonamide:與PABA相似,與之競爭和Enzyme的作用,使folic acid 無法生成,抑制細菌的生長。動物不會合成folic acid (直接攝取)。

  • Antagonism(拮抗性):兩種藥物一同使用時,其中一種會干擾另一種藥物之作用。
slide30
細菌抗藥性的種類

一、產生分解抗生素的酵素

eg. S. aureus產生b-lactamase

二、改變通透性

eg. tetracycline 在susceptible cell內聚積,而不在resistant cell 內聚積。

三、改變藥物所結合之標的物(target)結構。

eg. aminoglycoside-resistant cell, 改變 30S上受體結構。

四、改變代謝途徑

eg. sulfonamide-resistant bacteria 不再合成folic acid,所以用不到 PABA。

slide31
細菌抗藥性的種類

五、酵素的性質改變

eg. sulfonamide-susceptible cells 其tetrahydropteroic acid synthetase與

sulfonamides具有較強之結合力;而在resistant cells,該enzyme與PABA有

較強之結合力。

slide32
抗藥性從何而來?

一、突變

二、從plasmid得到resistant gene (RTF: Resistance Transfer Factor).

penicillin g
Penicillin G之分子結構

6-APA

Can be substituted

with procaine,

benzathine,

or potassium