The Discovery of Penicillin

The application of antibiotics for the treatment of diseases is not new. [30] In Chinese folk medicine, the healing properties of curd cheese with mouldy beans had been known for at least 2,500 years. From records we know that the Romans and Egyptians used mouldy bread for the treatment of diseases. The peoples of Sudan and Nubia also used antibiotics from a very early date on. Fluorescence spectra of bones from those times show strong agreement with the spectra from bones of patients, who have been treated with tetracyclines. 

In 1877, Louis Pasteur discovered that bacteria were able to inhibit the growth of other germs. For this phenomenon, the French Army doctor Jean Antoine ViUemin (1828-1892) coined the term Antibios . 

Already inl889, the German bacteriologist Rudolf Emmerich (1852-1914) and the German chemist Oscar Low (1844-1941) had isolated a bactericidal 

As a result, one of mankind s greatest discoveries, which has saved up to the present the lives of more than 100 million people, occurred only by chance not until 1928 - through the carelessness ofthe Scottish pharmacologist Alexander Fleming (Fig. 5.24). A fungal spore had contaminated an unattended and almost discarded culture of Staphylococcus aureus in a Petri dish, and had created a zone of inhibition to bacterial growth. 

Fleming could show that penicfllin was non-toxic in animal experiments and not damaging towards human cells. Initially, it was impossible to isolate the active compound in pure form and to determine its structure. Up to the outbreak of the Second World War, no significant progress was made, despite considerable effort. 

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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). 

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... 

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. 

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],... 

For the story of the discovery of penicillin, see W. Howard Hughes, Alexander Fleming and Penicillin, Crane Russak, 1977 R. Bud, Penicillin Triumph and Tragedy, Oxford University Press, Oxford, UK, 2007. 

Plants remained essentially the sole source of natural product drugs until well into the 20th century. Then in 1928 the discovery of penicillin hy the Scottish bacteriologist Sir Alexander Fleming (1881-1955) opened an entirely new area of research in the held of... 

Since the discovery of penicillin, an enormous number of antibiotic compounds have been isolated. They have found uses both in treatment of human disease and in various aspects of agriculture, including treatment of animal and plant diseases, and as feed additives to promote growth of animals. Some antibiotics such as tylosin were developed specifically for agricultural use. 

Since the discovery of penicillin, there have been attempts to modify the structure in order to increase their activity against less susceptible bacterial stains or to make it less sensitive to fylactamases that render it inactive. The synthetic modifications to the natural product penicillins can be classified into four different generations. 

The discovery of penicillin and its successful application in World War II inspired the antibiotic era, and a broad search for other cures for infectious diseases. Cancer has a totally different cause, as it arises through the malignant mutation of normal cells instead of from the actions of bacterial or other outside organisms. Penicillin destroys the bacteria cell walls, but not the mammalian cell membranes. Unless a dmg could be found that could tell the difference between a normal cell and a cancer cell, then it was not clear that there would be an effective cancer drug, that is until the first report by Goodman in 1946 that nitrogen mustard, developed as a war gas, was an effective chemotherapeutic for human leukemia. 

Many of the significant advances in drug discovery over the past one and a half centuries owe their success to serendipity the discovery of penicillin (discussed in chapter 9) is a legendary example of its importance. However, many other drugs were also discovered by accident. Continuing the theme of epilepsy from section 3.2.1 provides additional examples of serendipity and drug discovery. 

The discovery of penicillin placed NPs back on the agenda of all the major pharma companies. Improved methods of production were developed and chemically modified penicillin analogues, with improved clinical value, were patented and widely adopted. Such was the optimism engendered by penicillin that it was rashly predicted that bacterial diseases would eventually be eradicated from the human population. Anyone with a reasonable knowledge of evolution and of NPs would have been surprised had that prediction come true. 

Why devote so much space to the discovery of penicillin Simply because penicillin was the first NP to be made in massive amounts in factory scale fermentations, because of its remarkable biomolecular properties. This showed, for the first time, that microbi-ally produced NPs were economically accessible to large populations of humans and that chemists had no monopoly on synthetic methods for the pharmaceutical industry. The story also tells us that a worldwide search for cultures best suited to making penicillin showed that it is the rare organism that makes antibiotics in large amounts, a conclusion confirmed by the next part of the story of antibiotics. 

Lax E. (2005). The mould in Dr Florey s coat—the remarkable true story of the discovery of penicillin. Abacus, London. 

EHRLICH, PAUL (1854-1915). A native uf Silesia, Enrlich is considered the founder of the science of chemotherapy, or the treatment of diseases by chemical agents. He did fundamental work on immunity, which earned him the Nobel prize in medicine in 1908. and also developed the famous neoarsphenamine (salvarsan or 606) treatment for syphilis (1910). which was no) improved upon until the discovery of penicillin. 

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 discovery of important anti-infectives is not limited to antibacterial or antifungal antibiotics (see Chapter 45) from microbial sources. Long before the discovery of penicillin, it was known... 

Scottish bacteriologist Sir Alexander Fleming, corecipient, with Ernst Boris Chain and Sir Howard Walter Florey, of the 1945 Nobel Prize in physiology or medicine, for the discovery of penicillin and its curative effect in various infectious diseases. ... 

Fleming [63], Chain [64,65], Florey [66,67] and Heatley [68] led to the discovery of penicillin, still the treatment of choice for syphilis after all these years. 

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