The Discovery of Cephalosporins

At the beginning ofthe 1950s, resistance towards penicillin appeared for the first time on a larger scale. In particular. Staphylococci were more prone to develop resistance. Their penicillinases caused deactivation of many penam antibiotics. Cepham antibiotics with modified basic skeletons and altered side-chains offer an interesting starting point to address this issue. [26] Although a solution to this problem had already been discovered, it required several more years before effective remedies could be provided. 

29 The structure of cephalosporin C was also confirmed by a simultaneous publication of the X-ray crystal analysis by Dorothy Crowfoot Hodgkin (1910-1994).[35] 

---

AH cephalosporins found in nature (Tables 1 and 2) have the D-a-aminoadipic acid 7-acyl side chain (21). AH of these compounds can be classified as having rather low specific activity. A substantial amount of the early work in the cephalosporin area was unsuccessfiiHy directed toward replacing the aminoadipic acid side chain or modifying it appropriately by fermentation or enzymatic processes (6,22). A milestone ia the development of cephalosporins occurred in 1960 with the discovery of a practical chemical process to remove the side chain to afford 7-ACA (1) (1). Several related processes were subsequendy developed (22,23). The ready avaHabHity of 7-ACA opened the way to thousands of new semisynthetic cephalosporins. The cephalosporin stmcture offers more opportunities for chemical modification than does that of penicillins There are two side chains that especiaHy lend themselves to chemical manipulation the 7-acylamino and 3-acetoxymethyl substituents. 

Azetidin-2-ones are the most extensively studied derivatives of azetidine, largely as a result of the discovery of the antibacterial properties of penicillins, cephalosporins and... 

Cephalosporins have a 3,6-dihydro-2//-l,3-thiazine nucleus, and some of their total syntheses start from 6//-l,3-thiazines. Since the discovery of the cephalosporins by Brotzu in 1943 and the enormous developments occuring in the chemistry of these antibiotics since the 1940s, the 1,3-thiazine nucleus has become one of the most important six-membered heterocycles. Cephalosporins now exceed penicillins in importance and presently account for 31% of the world market of all antibiotics. 

Further, the discovery of 7-a-methoxy cephalosporins [5] from Streptomyces in 1971, carbapenems [6], thienamycin [7], clavulanic acid [8], sulbactum [9] as well as the totally synthetic oxapenems [10], oxacephams [11], and other bicyclic (3-lactams stimulated the search for novel antibiotics. More recent dedicated efforts to find new active molecules and modify the penicillin and cephalosporin structure have resulted in the discovery of simple monocyclic (3-lactams such as norcardicins and monobactams [12, 13]. Yet another dimension has been added to the (3-lactam research with the recent discovery of tricyclic (3-lactam antibiotics called trinems [14]. Thus, (3-lactam antibiotics in general can be classified into several groups based on their structures (Fig. 1). 

The development of antibacterial chemotherapy during the past 75 years has spearheaded the successful use of today s drugs to combat bacterial infections. Studies in (3-lactam chemistry were stimulated when (3-lactam ring, the four membered heterocycle, was recognized as a key structural feature as well as a key therapeutic feature of the bicyclic (3-lactam antibiotics such as penicillins, cephalosporins, and other classical antibiotics. The last two decades have registered the discovery of several nonclassical bicyclic (3-lactam antibiotics, e.g., thienamycin and carba-penems of natural origin like olivanic acids, carpetimycin, pluracidomycin, and aspareomycins. 

After the discovery of penicillins and cephalosporins as classical (3-lactam antibiotics and clinically useful active agents, the past few decades have witnessed a remarkable growth in the field of (3-lactam chemistry [1, 2]. The need for potentially effective (3-lactam antibiotics as well as more effective (3-lactamase inhibitors has motivated synthetic organic and medicinal chemists to design new functionalized 2-azetidinones. Besides their clinical use as antibacterial agents, these compounds have also been used as synthons in the preparation of various heterocyclic compounds of biological significance [3-7]. The potential use of some... 

The discovery of penicillin by Sir Alexander Fleming in 1929 has been recognized as one of the most fortunate discoveries in modem times [1], The (3-lactam ring is the key component of commonly used antibiotics such as penicillins, cephalosporins, carbapenems, and monobactams [2], The development of (3-lactam antibiotics... 

The successive discoveries of cephalosporin C (1945), cephamycin (1971), thienamycin (1976), clavulanic acid (1975), nocardicin (1976), sulfazecin (1981), etc. The structural diversity found in the natural compounds inspired the medicinal chemists for side-chain modifications of the penam and penem cores (see Section 2.03.11). 

After the Second World War, the effort continued to find other novel antibiotic structures. This led to the discovery of the peptide antibiotics (e.g. bacitracin (1945)), chloramphenicol (Fig. 10.72) (1947), the tetracycline antibiotics (e.g. chlortetracycline (Fig. 10.71) (1948)), the macrolide antibiotics (e.g. erythromycin (Fig. 10.73) (1952)), the cyclic peptide antibiotics (e.g. cycloserine (1955)), and in 1955 the first example of a second major group of (3-lactam antibiotics, cephalosporin C (Fig. 10.41). 

Considerable work went into modification of the strain (through the use of X-rays or UV light to induce mutations) and improvements were made in the technology of isolation and purification. However, the mould was much more difficult to handle and would not accept alternative side-chain precursors as did Penicillium chrysogenum hence, it was impossible to prepare semi-synthetic cephalosporins by this route. In addition, the discovery of methicillin with its resistance to penicillinases negated the advantages of cephalosporin C, and for a while it appeared that this new class of antibiotics was doomed. 

---