From coincidence to discovery: Penicillium notatum
In the late 19th century, a greater understanding of disease led researchers to seek treatments to kill or inhibit the growth of microbes. This proved elusive until the accidental discovery of penicillin in 1928 by Alexander Fleming. A culture plate of Staphylococcus bacteria from an experiment was left on his bench during a two-week vacation and became contaminated with Penicillium notatum mold. When Fleming returned and found the plate, he noticed that surrounding the yellow-green mold growth was a distinct clear halo. Since the Staphylococcus bacteria was able to grow across the plate except near the section contaminated with mold, Fleming postulated that Penicillium was somehow capable of inhibiting bacterial growth.
Experiments, first application and Nobel prize
It took another 11 years for an Oxford University research team, under the guidance of biochemists Ernst Chain and Howard Florey, to isolate and purify penicillin. In a 1940 Lancet paper they reported that mice injected with a lethal dose of Streptococcus could be cured with penicillin. Initial testing on patients began immediately, and in a 1943 Lancet article Florey described incredible success using penicillin to treat wounded soldiers in North Africa. European production of penicillin was limited by fighting during World War II, but by D-Day, June 6, 1944, US pharmaceutical companies were able to produce enough penicillin to treat all wounded British and American troops. Penicillin quickly became a primary treatment for pneumonia, diphtheria, syphilis, gonorrhea, scarlet fever, and many other infections. For “the discovery of penicillin and its curative effect in various infectious diseases” Fleming, Chain, and Florey received the Noble Prize for Medicine in 1945.
Antibiotics: classification according to spectrum of action
Antibiotics are a broad class of chemicals that are capable of either inhibiting growth or killing bacteria. They interfere with metabolic processes necessary for bacteria to grow, but do not typically harm human cells. There are several different classes of antibiotics with a variety of molecular targets. For example, both penicillin and vancomycin, obstruct cell wall synthesis in gram-positive bacteria causing them to lyse. Because they only affect gram-positive bacteria, penicillin and vancomycin are considered “narrow spectrum” antibiotics. Tetracyclines, on the other hand, are “broad-spectrum” antibiotics that act on both gram-positive and gram-negative bacteria to impede protein production by binding to ribosomes and reducing their activity.
Derivatives of penicillin
Following the discovery of penicillin from Penicillium mold, researchers were able to identify and isolate new antibiotics from soil bacteria and fungi. An article in the New England Journal of Medicine reported that between 1940 and 1970, ten entirely different classes of antibiotics, each with unique targets or modes of action were identified. However, from 1970 until the late 1990’s all new antibiotics were derivatives of these existing classes. For example, based on the chemical structure of penicillin, several synthetic variants have been produced that keep the pharmacologically active part of the chemical, but circumvent resistance by modifying other parts of the structure. Ampicillin and amoxicillin are penicillin-variants developed in this manner which also turned out to be broad-spectrum antibiotics.
Research and development of new antibiotics (decline)
A 2006 study in Nature Biotechnology found that since 1998 only four antibiotics exhibiting a new mechanism or significantly different chemical structure have been approved by the US Food and Drug Administration (FDA). They also found that only six antibiotics were in phase 2 or phase 3 clinical trials as compared to 313 other drugs, and that only eight of fourteen major pharmaceutical companies they surveyed appeared to be conducting antibiotic research and development.