- 作者: Arnold L. Demain
- 作者服務機構: 美國麻省理工學院生物系醱酵微生物學實驗室
- 中文摘要:
Penicillin在六十幾年前被發現時是第一個戶β-lactam抗生素至今,它的重要性仍然比其他此類抗生素高。很明顯地,
雖然β-lactam抗生素已經使用了六十多年,但它們的重要性卻越來越穩固,似乎沒有人會認為它們有被放棄的可能。
直到最近,β-lactam抗生素的交易仍然佔全世界抗生素市場的最大比率。β-lactam抗生素包括Penicillin類如Pe-
nicillin G,Penicillin V,ampicillin,cloxacillin,fnpiperacillin等;cephalosporin類如cephalothin,cephaloridine,cephalexin,和
cefaclor等;以及cephamycin類如cefoxitin。另外,β-lactam抗生素尚包括最近新發展出來而尚未分類的結構,monobac-
tams如aztreonam;混合藥劑augmentin中的成分之一,clavulanic acid;和混合藥劑primaxin(或tienam)成分之一的thienamy-
cin(已被化學改造為imipenem)。
正統的β-lactam抗生素可被分為拒水性和親水性等兩類醱酵產物。拒水性β-lactam抗生素有benzylpenicillin(pe-
nicillin G)和phenoxy methylpenicillin(penicillin V),它們分別含有非極化側鏈結構如phenylacetate和phenoxyacetate,而且
皆由絲狀黴菌所產生其最知名者為Penicillium chrysogenum。拒水性penicillin的主要抗菌範圍在革蘭氏陽性菌。親水性β-
lactam抗生素有由黴菌產生的Penicillin N,cephalosporin,和由放線菌或單細胞細菌產生的7-α-methoxycephalosporin(ce-
phamycin),它們都含有極化側鏈結構,D-α-aminoadipate。
我們可寫出penicillin和cephalosporin生物合成的系列化學反應,但沒有一種微生物能包含所有的反應。所有penicillin
和cephalosporin的生物合成途徑皆有共同的前三步驟,而且所有cephalosporin的生物合成途徑皆經過deacetylcephalospo-
rin C的步驟。但在不同的生產菌中,仍有許多不同的次要生物合成反應步驟。
β-Lactam抗生素的生產在營養不平衡和生產菌的低生長率條件下最好。營養不平衡可由限制碳源、氮源和磷源所造
成。除此之外,lysine和methionine等胺基酸亦可產生對某些微生物生產penicillin或cephalosporin的明顯影響。例如由me-
thionine誘導的某些合成?,尤其是第一個?,ACV合成?,是methionine促進C. acremonium生合成cephalosporin的基
礎。而lysine對homocitrate合成?的抑制作用則是lysine抑制Penicillium chrysogenum生合成penicillin的機轉。但另一方
面,lysine可促進Streptomyces clavuligerus生合成cephamycin則是因為lysine可被分解為合成cephamycin的前驅
物,α-aminoadipic acid之故。各種不同合成?皆可被一些營養成分中如碳源、氮源和磷酸鹽所抑制,此乃說明了含有豐富
葡萄糖或甘油,氨鹽和無機磷酸鹽的平衡生長培養基所造成對β-lactam抗生素生合成的負面影響。
g - 英文摘要: The discovery of penicillin was announced over 60 years ago. It was the first β-lactam antibioticand the importance of this group is greater today than it has ever been. It is clear that even at 60 yearsof age, β-lactam are going strong and no one contemplates their early retirement. Currently, sales of β-lactam compounds form the largest share by far of the world's antibioticmarket. The β-lactam antibiotics include penicillins such as penicillin G, penicillin V, ampicillin, cloxacillin,and piperacillin; cephalosporins such as cephalothin, cephaloridine, cephalexin, and cefaclor; and cephamy-cins such as cefoxitin. In addition, β-lactam antibiotics include the more recently developed nonclassicalstructures such as monobactams, including aztreonam; clavulanic acid, which is a component of thecombination drug augmentin; and thienamycin, which is chemically transformed into imipenem, a com-ponent of the combination drug known as primaxin (or tienam). The classical β-lactam antibiotics can be divided into hydrophobic and hydrophilic fermentationproducts. The hydrophobic members, e.g. benzylpenicillin (penicillin G) and phenoxymethylpenicillin(penicillin V), contain non-polar side chains, e.g. phenylacetate and phenoxyacetate, respectively, and aremade only by filamentous fungi; the best known of these is Penicillium chrysogenum. The antibacterialspectrum of the hydrophobic penicillins is essentially Gram-positive. The hydrophilic types are penicillinN, cephalosporins and 7-α-methoxycephalosporins (cephamycins) which are made by fungi, actinomycetesand unicellular bacteria. They all contain the polar side chain, D-α-aminoadipate. We can draw a sequence of reactions which describes the biosynthesis of all penicillins and cephalo-sporins, however the total sequence exists in no one microorganism. All penicillin and cephalosporinbiosynthetic pathways possess the first three steps in common and all cephalosporin pathways go throughdeacetylcephalosporin C. However, there are many subsequent biosynthetic reactions which vary in thedifferent producing organisms. Production of β-lactam antibiotics occurs best under conditions of nutrient imbalance and at lowgrowth rates. Nutrient imbalance can be brought about by limitation of the carbon, nitrogen or phosphorussource. In addition to these factors, amino acids such as lysine and methionine exert marked effects onproduction of penicillins and/or cephalosporins by some microorganisms. Induction of some of the synthetases, especially the first enzyme, ACV synthetase, by methionmeis the basis of the methionine stimulation of cephalosporin C synthesis in C. acremonium. Inhibition ofhomocitrate synthase is the mechanism involved in lysine inhibition of penicillin synthesis in Penicilliunchrysogenum. On the other hand, lysine stimulation of cephamycin production in Streptomyces clavuligerusis due to its breakdown to the limiting precursor, α-aminoadipic acid. The various synthetases are repressedand/or inhibited by nutrients such as sources of carbon, nitrogen and phosphate accounting for thenegative effects of a balanced growth medium rich in glucose or glycerol, ammonium salts and inorganicphosphate.
- 中文關鍵字: beta-lactam antibiotics; secondary metabolism; Cephalosporium; Penicillium; Strep-tomyces.
- 英文關鍵字: --