Antibiotics

The term antibiotic was first used in 1899 by the botanist Marshall Hall, following the coining of the term antibiosis ten years earlier by French scientist Paul Vuillemin. Antibiosis referred to the idea that living organisms might produce substances that were antagonistic to one another, an idea first suggested by Louis Pasteur in 1877. In the late nineteenth century, many observations of antibiotic action among microorganisms were reported,rift gold but unfortunately the significance of these observations was not appreciated at the time.

In the history of antibiosis, an observation by Alexander Fleming (1881–1955), a bacteriologist at St. Mary’s Hospital in London, proved to be the turning point. In the late summer of 1928, Fleming went to his laboratory during the holiday to inspect culture plates awaiting disposal. He noticed one that had been accidentally contaminated with a mold, or fungus, around which bacterial growth had been inhibited. The bacteria were staphylococci and the fungus was Penicillium notatum. Fleming cultured it, fixed the plate in formalin vapor, and gave it the name penicillin. Fleming’s tests showed that the fungus could kill or inhibit the growth of a number of other organisms harmful to man. In a paper in 1929, Fleming mentioned the possible use of penicillin as an antiseptic in surgical dressings. There was further work in other laboratories interested in Fleming’s observation, but progress was limited because of the great instability of the material. The goal of isolating an effective preparation from the organism remained for the future.

In 1939, three other British scientists based in Oxford made the discovery that penicillin was effective inside the body as well as on its surface. Ernst Chain, Howard Florey, and Norman Heatley, embarked on its detailed investigation, urged on by the necessities of war. In 1940 Florey and Chain were able to make a dry, stable extract of penicillin, and the first trial was carried out on four mice on May 25 1940.

The first human received an injection of penicilin on January 27 1941, at the Radcliffe Infirmary in Oxford. The patient did not have an infection, but suffered a sharp rise in temperature after 3 hours. After removal of the pyrogen that caused the fever, enough active material was isolated to treat one ill patient. On February 12 1941, a London policeman who had a severe staphylococcal infection was the first sick patient to receive penicillin. After treatment for five days, the stock of penicillin was exhausted, and the patient relapsed and died. Over the following days further seriously ill patients were treated with varying degrees of success, and the results were published in August 1941.

By early 1942, small-scale production was being carried out in the U.K. by Imperial Chemical Industries Limited. However the investment needed to produce penicillin on a commercial scale was considerable and could not easily be found in a country at war. Florey and Heatley went to America to seek support. Penicillin was first made in the United States by the pharmaceutical company Upjohn in March 1942, using a culture supplied by the U.S. Department of Agriculture. Initial small-scale production was achieved using a surface culture method in bottles. On May 25 1943, the firm was asked to make penicillin for the military, and it began brewing the fungus in 120,000 bottles in a basement. By July 1943 the company had shipped its first batch of 100 vials, each containing 100,000 units of penicillin.

The process of surface culture in bottles had obvious limitations, and work began to develop a more efficient process that used deep culture in vat fermenters. The principle of the submerged culture method is to grow the fungus in large steel containers in a medium that is constantly aerated and agitated. Under these circumstances, the fungus grows throughout the body of the medium. Early problems in the operation of the method were overcome, and by 1949 fermenters with capacities up to 12,000 gallons were in use. Tens of thousands of species and mutants of Penicillium were examined in the search for ones that produced the highest yields of penicillin. Eventually the highest yields were obtained from a strain of Penicillium chrysogenum, originally found growing naturally on a moldy melon. As a result yields have increased 2000 times since the original small-scale manufacture. Solving the complex microbiological, chemical, and engineering problems involved in the largescale manufacture of penicillin required a collaborative effort. By 1944, 20 American and 16 British academic and industrial groups were working on the problem. The first large delivery, consisting of 550 vials of 100,000 units of penicilin each, was made to the U.S. Army in February 1944. Its initial use was in the treatment of gonorrhea; widespread use of penicillin in the treatment of life-threatening conditions such as pneumonia only occurred later when sufficient supplies became available. With large-scale manufacture the price dropped dramatically from $20.05 per 100,000-unit vial in July 1943 to just $0.60 per vial by October 1945.

Full understanding of the mode of action of penicillin only emerged slowly and awaited developments in both biochemistry and bacteriology. The involvement of the cell wall was recognized early on, but even in 1949 Chain and Florey concluded, ‘‘No complete picture of how penicilin acts in vivo can be drawn on the evidence available.’’ Penicillin inhibits an enzyme that catalyzes one of the biochemical steps in the synthesis of mucopeptide, the rigid component of the cell wall. In the absence of the enzyme inhibited by penicillin, links between the peptide molecules fail to occur. When penicillin in sufficient concentration comes into contact with penicillin-sensitive organisms,rift gold it binds to the cell wall. As cell division takes place, defects occur in the rigid component of the wall. Coupled with high internal osmotic pressure, the cell then bursts, or lyses. Penicillin is therefore only active against growing bacteria and only those sensitive to it. Some bacteria contain plasmids that make them resistant to penicillin.

In subsequent years a large number of variants of penicillin were developed. Some of these were naturally produced, some were semisynthetic, and others were entirely synthetic. The search for effective antibacterial substances was widened, and the stage was set for the discovery of a wide range of new antibacterial substances in the post-World War II years.