Semisynthetic p lactam antibiotics

The total U.S. antibiotic market for 1990 was about 4.73 biUion, 233 million of that was tetracyclines. The development of the semisynthetic P-lactam antibiotics (see Antibiotics, P-LACTAMs) and emergence of resistance to the tetracyclines has steadily diminished the clinical usefulness of tetracyclines. 

Use antibacterial, semisynthetic p-lactam antibiotic, derivative of ampicillin (prodrug for ora application)... 

Cephalothin is a semisynthetic P-lactam antibiotic prepared by the reaction of thio-phene-2-acetyl chloride with 7-aminocephalos-poranic acid (7-ACA). The cephalosporanic nucleus is obtained from cephalosporin C which is produced by a fungus identified as Cephalosporium acremonium No. +9137 (Imperial Mycologi-cal Institute, England), or strains thereof. 

Substituted hydantoin derivatives have been used as precursors for d- and L-amino acids in chemical synthesis. However, they are hydrolyzed enantioselectively by the enzymes named hydantoinases some act specifically on D-5-substituted hydantoins, and others on the L-isomers. N-Carbamoyl amino acids formed are also hydrolyzed enantiospecifically by N-carbamoyl amino acid amidohydrolases to produce d- or l-amino acids (Fig. 17-15). Since the Kanegafuchi Chemical Industry, Japan, commercialized an enzymatic procedure for the production of D-p-hydroxyphenylglycine, which is a building block for the semisynthetic P-lactam antibiotic amoxycillin, various processes for amino acid production by means of hydantoinases have been developed 131 133. ... 

The cost of 6-APA, ampicillin, and amoxicillin is invariably linked to that of penicillin G. 6-APA remains one of the cheapest raw starting materials available for the preparation of semisynthetic penicillins and other related P-lactam antibiotics. 

Figure 6.37 shows the two-dimensional structure of cephalosporin C, a compound first isolated from mold cultures of Cephalosporium acremonium in 1948. Cephalosporin C exhibits weak antibacterial effect, but the modification of side chains of the molecule generates cephalosporins having diverse antibacterial activity [105]. Cephalosporins are p-lactam antibiotics, semisynthetically produced from cephalosporin C. 

T. Yamana, A. Tsuji, and Y. Mizukami, Kinetic approach to the development in P-lactam antibiotics. I. Comparative stability of semisynthetic penicillins and 6-aminopenicillanic acid in aqueous solution, Chem. Pharm. Bull. 22, 1186-1197(1974). 

In the 1970s and the 1980s, the pathways to the penicillins and the cephalosporins including cephamycin C were worked out especially after cell-free systems became available [59]. Late in the 1970s came reports on the production of P-lactam antibiotics which were neither penicillins nor cephalosporins. The most important was clavulanic acid from streptomycetes, which possessed only weak antibiotic activity but was an excellent inhibitor of P-lactamase [60]. It became a blockbuster compound by being coformulated with broad-spectrum semisynthetic penicillins which are susceptible to P-lactamase, for example, with amoxycillin, the combination is known as Augmentin. 

For both the clinician and patient, an allergic reaction elicited by a p-lactam antibiotic is probably considered the archetypal drug allergy but a range of other antibiotics, both naturally occurring and semisynthetic, and a number of other antimicrobials of varied origin and nature also... 

Other Reactions. The reaction of Thydioxybenzaldehyde with sodium cyanide and ammonium chloride, Strecker synthesis, yields /J-hydroxyphenylglycine [938-97-6] a key intermediate in the manufacture of semisynthetic penicillins and cephalosporins (see Antibiotics, p-LACTAMs). 

Pharmaceuticals. -Hydroxybenzaldehyde is often a convenient intermediate in the manufacture of pharmaceuticals (qv). For example, 2-(p-hydroxyphenyl)glycine can be prepared in a two-step synthesis starting with -hydroxybenzaldehyde (86). This amino acid is an important commercial intermediate in the preparation of the semisynthetic penicillin, amoxicillin (see ANTIBIOTICS, P-LACTAMs). Many cephalosporin-type antibiotics can be made by this route as well (87). The antiemetic trimethobenzamide [138-56-7] is convenientiy prepared from -hydroxybenzaldehyde (88) (see Gastrointestinal agents). 

Use antibacterial in combination with 3-lactam antibiotics, semisynthetic P-iactamase inhibitor... 

The bacterium Staphylococcus aureus, which is a major cause of infection in the developed countries, is now resistant to most antibiotics. It is usually present on the skin, where it causes no problems, but it can invade the body through cuts and wounds, including those caused by surgery. These bacteria are now prevalent in many hospitals, so that infection is a major problem for the medical staff in hospitals. The resistant bacterium is known as methicillin-resistant Staphylococcus aureus (MRSA). It is also known in the mass media as the super bug . Penicillin kiUs bacteria because the P-lactam group in the antibiotic inhibits a reaction that is essential for bacterial ceU wall production. Consequently, the bacteria cannot proliferate. Resistance to penicillin in many bacteria is due to production of an enzyme, p-lactamase, that degrades P-lactams. The antibiotic methicillin is one of a group of semisynthetic penicillins in which the P-lactam group is not... 

The penicillins, from the fungus Penicillium chryso-genum, are the oldest and most widely used antibiotics. They are formed through stepwise build-up from a tripeptide (ACV) derived from a-Amino adipic acid, cysteine, and valine. Successive oxidation steps form the p-lactam and close the thiazolidine ring to form isopenicillin N. Action of an acyltransferase then yields penicillin G (Fig. 47). Alternatively, hydrolysis of isopenicillin N (or penicillin G) yields 6-aminopenicillanic acid, a key precursor for the wide range of semisynthetic pencillins used therapeutically. 

Penicillin (or benzylpenicillin) (32a) (R = CH2Ph) was first dicovered by Sir Alexander Fleming in 1929, who isolated the antibiotic from the fungal strain Penicillium notatum (see Introduction, p. 4). Penicillin is valuable to combat bacterial infections in man and animals. It was first manufactured commercially in 1945 and the first semisynthetic penicillins were introduced in 1954. The penicillins (32) have a common structural feature, namely a p-lactam ring fused to the... 

The setting up of new biotechnology companies (Section 1.4.2) was the key event for the development of biopharmaceuticals based on recombinant technologies. Antibiotic manufacture had been established before this (Section 1.3). Antibiotics are still the most important strategy against bacterial infections. The world production of antibiotics is estimated at over 60000 tons per aimum, valued at more than 30 billion per year [128, 129]. For the synthesis of semisynthetic penicUlins and cephalosporins, the fermentation products penicillin G and cephalosporin, respectively, are hydrolyzed by immobilized enzymes to yield the acid form with the intact P-lactam ring as the active principal 6-APA, 7-ACA, or 7-aminodeacetoxy cephalosporanic acid (7-ADCA). 

Together with the penicillins, the cephalosporin p-lactam antibacterials are the most widely used antibiotics for the treatment of common infections. The origin of cephalosporin antibiotics dates back to 1948 with the demonstration of antimicrobial action in a fungal extract from what was then called Cephalosporium acremonium. The Cephalosporium genus is now known as Acremonium. The cephalosporins used in medicine today are semisynthetic derivatives of the natural antibiotic cephalosporin C. Soon after cephalosporins were introduced into clinical use, adverse reactions including apparent hypersensitivity reactions and obvious anaphylactic responses began to appear, and although their similar structural features to the penicillins... 

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