History of the development of antibiotics

The great modern advances in chemotherapy have come from the chance discovery that many microorganisms synthesize and excrete compounds that are selectively toxic to other microorganisms. These compounds are called antibiotics and have revolutionized medicine. The period since World War II has seen the establishment and extremely rapid growth of a major industry, using microorganisms for the synthesis of, amongst other compounds, chemotherapeutic agents. The development of this industry has had a dramatic and far-reaching impact. Nearly all bacterial infectious diseases that were, prior to the antibiotic era, major causes of human death have been brought under control by the use of chemotherapeutic drugs, including antibiotics. In the United States, bacterial infection is now a less frequent cause of death than suicide or traffic accidents.

The first chemotherapeutically effective antibiotic was discovered in 1929 by Alexander Fleming (1881–1955), a British bacteriologist, who had long been interested in the treatment of wound infections. On returning from a vacation in the countryside, he noticed among a pile of petri dishes on his bench one that had been streaked with a culture of Saphyloccocus aureus which was also contaminated by a single colony of mold . As Fleming observed the plate, he noted that the colonies immediately surrounding the mold were transparent and appeared to by undergoing lysis. He reasoned that the mould was excreting into the medium a chemical that caused the surrounding colonies to lyse. Sensing the possible chemotherapeutic significance of his observation, Fleming isolated the mold, which proved to be a species of Penicillium, and established that culture filtrates contained an antibacterial substance, which he called penicillin .

Although it has often been suggested that many bacteriologists must have observed petri dishes that were similarly contaminated and therefore similar in appearance to Fleming's dish, such speculation is undoubtedly false. As subsequent experiments have shown, a highly unusual series of events must have occurred in order to produce the results seen on Fleming's plate: contamination must have occurred at the time the plate was streaked with bacteria (prior growth of either would have prevented growth of the other in the immediate vicinity); the inoculated petri dish must not have been incubated (if it had been the bacterium would have outgrown the mold); the room temperature of the laboratory must have been below 68°F [20° C] (a temperature that probably did occur during a brief cold storm in London in the summer of 1928).

Penicillin proved to be chemically unstable and Fleming was unable to purify it. Working with impure preparations, he demonstrated its remarkable effectiveness in inhibiting the growth of many Gram-positive bacteria, and he even used it with success for the local treatment of human eye infections . In the meantime, the chemotherapeutic effectiveness of other, non-antibiotic compounds such as sulfonamides had been discovered, and Fleming, discouraged by the difficulties in purifying penicillin, abandoned further work on the problem.

Ten years later a group of British scientists headed by H.W. Florey (1898–1968) and E. Chain (1906–1979) resumed the study of penicillin. Clinical trials with partly purified material were dramatically successful. By this time, however, Britain was at war; and the industrial development of penicillin was undertaken in the United States, where an intensive program of research and development was begun in many laboratories. Within three years, penicillin was being produced on an industrial scale. Today it remains one of the most effective chemotherapeutic agents for the treatment of many bacterial infections.

Rather than being a single substance, penicillin turned out to be a class of compounds. The various penicillins vary with respect to the chemical composition of their side chain. The penicillin that was first isolated in Peoria, Illinois, designated penicillin G, carried a benzyl side chain. The penicillin isolated soon after in England, designated penicillin F, carried an isopentanyl side chain. By varying the composition of the fungal growth media, a variety of penicillins collectively termed biosynthetic penicillins, have been synthesized. Penicillin G proved the most successful and later it became possible to remove the side chain and replace it by a variety of chemical substituents, thereby producing semisynthetic penicillins. For example, penicillin V is resistant to acid and therefore can be administered orally because it is not inactivated in the stomach; ampicillin is also acid resistant and also effective against enteric bacteria; oxacillin is resistant to the action of B-lactamase, the enzyme produced by certain "penicillin-resistant" strains of bacteria.

The remarkable chemotherapeutic efficacy of penicillin for certain bacterial infections, primarily those caused by Gram-positive bacteria, prompted intensive research into new antibiotics. In the 1940s, a second clinically important antibiotic, streptomycin, effective against both Gram-negative bacteria and Mycobacterium tuberculosis, was discovered by A. Schatz and S.Waksman . This was the first example of a broad-spectrum antibiotic. Other antibiotics with even broader spectra of activity, such as the tetracyclines, were subsequently discovered. The search for new antibiotics remains an empirical enterprise. So far, they have proved very effective as antibacterial agents, although some bacteria do acquire resistance to antibiotics, so there is a continuous search for new and effective antibacterial agents. Antibiotics have proved less effective in the treatment of fungal infections. Antifungal antibiotics, such as nystatin and amphoterecin B are considerably less successful therapeutically than their bacterial counterparts, at least in part because their toxicity is far less selective. There are no known antiviral antibiotics.

Since 1945, thousands of different antibiotics produced by fungi , actinomycetes or unicellular bacteria have been isolated and characterized. A small fraction of these are of therapeutic value. Their nomenclature is complicated as one antibiotic may be sold under several different names. For example in the United States the compound, which in Europehas the generic name rifampicin, is called rifampin. Its proper chemical class name is rifamycin and it is also sold under the trade names Rifactin and Rifadin, among others.

See also Bacteria and bacterial infection; Fungicide; History of microbiology; History of public health; Streptococci and streptococcal infections; Sulfa drugs