Penicillin, discovery

Peanut oil, composition of, 1062 Pedersen, Charles John, 666 Penicillin, discovery of, 824-825 Penicillin V, specific rotation of, 296 stereochemistry of, 321 Penicillium notation, penicillin from. 824... 

Semisynthetic Penicillins. Just as the independent lines of inquiry of Dubos, Waksman, and the Oxford group converged to open the antibiotic era, the period of semisynthetic penicillin discoveries was initiated by a similar convergence. As an outgrowth of the early observation that the chemical nature of the penicillins produced by fermentation was influenced by the composition of the growth medium, the preparation of biosynthetic penicillins was accomplished by adding substituted phenyl-acetic acid derivatives (and related structures) to penicillin fermentations. By this method Behrens and co-workers at the Eli Lilly Co. had by 1948 prepared some 30 penicillins modified in the acyl moiety (64). 

Penicillins. Since the discovery of penicillin in 1928 as an antibacterial elaborated by a mold, Penicillium notatum the global search for better antibiotic-producing organism species, radiation-induced mutation, and culture-media modifications have been used to maximize production of the compound. These efforts have resulted in the discovery of a variety of natural penicillins differing in side chains from the basic molecule, 6-aminopenici11anic acid [551-16-6], These chemical variations have produced an assortment of dmgs having diverse pharmacokinetic and antibacterial characteristics (see Antibiotics, P-lactams). 

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. 

Penam Sulfone B-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of p-lactamase inhibitors based on the readily accessible penicillin nucleus. An early success was penicillanic acid sulfone, (2(5)-cis)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-a2abicyclo [3.2.0]heptane-2-carboxylic acid [68373-14-8] (sulbactam) (25, R = = H, R" = R" = CH ), CgH NO S. The synthesis (118), microbiology (119—121),... 

Landmarks in the development of penicillin are its discovery in 1929 (2) and the subsequent recognition in 1940 of the potential utiUty of penicillin for controlling antibacterial infections in animals (3) and shordy afterward in humans (4,5). The realization that penicillin was a usehil dmg occurred during WoddWar II (6). 

Following the discovery of penicillins, an extensive program for the screening of culture fluids and residual mycelial material commenced which resulted in the discovery of a large number of pyrazinones and related 1-hydroxy-2-pyrazinones with pronounced antibiotic character. Some examples are shown in Table 4. One of the earliest substances to be isolated, aspergillic acid (110 = OH, = Me, R = Et, R = R = H, R = Pr ), was found... 

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... 

In the post-World War II years, synthesis attained a different level of sophistication partly as a result of the confluence of five stimuli (1) the formulation of detailed electronic mechanisms for the fundamental organic reactions, (2) the introduction of conformational analysis of organic structures and transition states based on stereochemical principles, (3) the development of spectroscopic and other physical methods for structural analysis, (4) the use of chromatographic methods of analysis and separation, and (5) the discovery and application of new selective chemical reagents. As a result, the period 1945 to 1960 encompassed the synthesis of such complex molecules as vitamin A (O. Isler, 1949), cortisone (R. Woodward, R. Robinson, 1951), strychnine (R. Woodward, 1954), cedrol (G. Stork, 1955), morphine (M. Gates, 1956), reserpine (R. Woodward, 1956), penicillin V (J. Sheehan, 1957), colchicine (A. Eschenmoser, 1959), and chlorophyll (R. Woodward, 1960) (page 5). ... 

The discovery and production of antibiotics has been of tremendous importance to human and animal health care. Prior to their discovery about half a century ago, many bacterial infections caused debilitating diseases and fatalities were high. The discovery of antibiotics was a major step in the treatment of infectious diseases, especially those caused by bacteria. Today about 50,000 tonnes of antibiotics are produced annually. About a third of this consists of penicillins, whilst tetracyclines make up about a quarter of the market. 

The discovery of antimicrobials is among the greatest medical achievements of the twentieth century. Prior to the antimicrobial era, patients who contracted common infectious diseases developed significant morbidity or perished. The discovery of penicillin in 1927, followed by the subsequent discovery of other antimicrobials, contributed to a significant decline in infectious disease-related mortality during the next five decades. However, since 1980, infectious diseases related mortality in the United States have begun to increase, in part owing to increases in antimicrobial resistance. 

The introduction of techniques for mutagenesis by UV irradiation or by the use of chemicals considerably extended the applications of microbial studies to nutrition (Davis, 1954-1955). Auxotrophic mutants were produced with nutrient dependencies not shown in the untreated parental strains (Beadle and Tatum, 1940). The fortuitous discovery of penicillin by Fleming and its successful use in the treatment of infections (Florey) promoted exhaustive research into its mode of action. Eventually it was established that penicillin prevented the proliferation of gram-positive bacteria by blocking the synthesis of their cell walls... 

Since the discovery of penicillin, research has produced a large number of different types of derivatives with the aim to extend antibacterial activity and to improve pharmacokinetic properties [1][2],... 

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