Issue Date: June 20, 2005
It's hard to imagine today, but in the days before antibiotics something as seemingly innocuous as an infected scratch could be deadly. That was before the discovery and development of penicillin, the first antibiotic, hailed by many as a miracle drug.
The roots of penicillin's reputation as a miracle drug were planted in 1942, when it pulled Anne Miller, a 33-year-old patient in a hospital in New Haven, Conn., back from the brink of death. She had developed a streptococcal infection that nearly killed her following a miscarriage. Her doctor had another patient, John F. Fulton, who was a medical professor at Yale and, more important in this situation, a friend of Howard W. Florey's, an Australian pathologist at the University of Oxford who was spearheading the development of penicillin as a drug. Fulton was able to pull strings to have 5.5 g of penicillin sent from the pharmaceutical company Merck in New Jersey, which was helping produce the drug. Within 24 hours of first receiving penicillin, Miller was on her way to recovery. She continued to receive penicillin during a monthlong convalescence before going home. She died in 1999, at the advanced age of 90.
The antibiotic properties of penicillin were first noticed in 1928 by Alexander Fleming, a microbiologist at St. Mary's Hospital in London, when he saw nothing but dead bacteria surrounding the mold, later identified as Penicillium notatum, that contaminated a culture of staphylococcus bacteria.
In later tests, Fleming found that the secretion from the mold was active against a number of bacteria, but he also found that penicillin--its composition then unknown--was unstable and its antibacterial activity short-lived. (Most of the penicillin administered is rapidly cleared from the body by the kidneys. In the early days, researchers would reuse penicillin extracted from urine.)
Fleming stopped working on penicillin in 1935, but his 1929 paper in the British Journal of Experimental Pathology was enough to catch the eye of Ernst B. Chain, a biochemist working with Florey, in 1938. Chain suggested to Florey that they undertake research on penicillin, but it was not until 1939 that they started the work in earnest.
FOLLOWING EXTENSIVE tests for absorption and toxicity in several types of animals, Florey's team conducted a series of experiments in which they injected mice with a normally lethal dose of virulent streptococci. Some of the mice received no penicillin, others received a single dose of penicillin, and still others received penicillin injections at regular intervals. In all the tests, the untreated mice died within 18 hours. In contrast, the treated mice survived.
The results were enough to send Florey searching for industrial partners who could help produce enough penicillin for human trials, because it was unlikely that the small-scale fermentation methods used at Oxford would yield enough. Unable to enlist any British companies, Florey and his coworker Norman Heatley came to the U.S. to drum up support among American companies. During his first appeal, Florey had only four takers--Merck, E. R. Squibb & Sons, Charles Pfizer & Co., and Lederle Laboratories.
The U.S. government became interested in penicillin after entering World War II. In previous wars, soldiers were more likely to die from infections that developed following wounds than from the wounds themselves. The government was anxious for anything that could reduce American casualties, and it made penicillin production a priority. The government's interest spurred more than 20 companies to join the efforts to produce sufficient quantities of penicillin. Production ramped up so much that by the invasion of Normandy in June 1944, companies were producing 100 billion units of penicillin per month.
Initially, penicillin was fermented in large, flat culture dishes resembling hospital bedpans. (The first ones were in fact hospital bedpans.) Andrew J. Moyer, a scientist at the U.S. Department of Agriculture laboratory in Peoria, Ill., and Heatley collaborated to improve the yield of penicillin. They experimented with such changes as adding "corn steep liquor" (a by-product of the extraction of cornstarch) and lactose rather than glucose to the fermentation. They also showed that penicillin could be produced in "deep culture," that is, submerged in the culture medium rather than at the surface.
Deep-culture fermentation, however, presented chemical engineering problems. Pfizer was the company that was able to overcome many of these challenges, applying expertise gained from the fermentation of products such as citric acid and gluconic acid. By the end of 1945, Pfizer was producing more than half the world's supply of penicillin.
Because production was so limited, initial stocks were earmarked for military use. The first large-scale human trials were conducted in military field hospitals. Florey and his friend Hugh Cairns, a fellow Australian who was a consultant surgeon to the British army, accompanied the army to North Africa in 1943. American doctors treated patients in the Pacific theater for infections related to compound fractures, soft-tissue wounds, and septicemia (blood infections).
In 1943, a surprising bit of information was revealed by purification studies in Britain and the U.S.: There isn't just one penicillin. Elemental analysis indicated that the groups were working with compounds with slightly different compositions. They had a common core but different side chains. The British researchers, who produced penicillin with surface fermentation, were working with penicillin F, now known to be 2-pentenylpenicillin. In contrast, the Americans were working with penicillin G, or benzylpenicillin.
Much of the work with penicillin was done while its chemical structure was still unknown. Chain, like Fleming before him, had assumed that penicillin was an enzyme and therefore a protein. Chain quickly realized when he tried to isolate and purify the active component that its properties made it more likely to be a small molecule. After it was known to be a small molecule, there were competing ideas of what its structure was likely to be, a debate that ended when Dorothy Hodgkin of the University of Oxford solved the crystal structure in 1945. The antibiotic, which contains a β-lactam group, is now known to wield its antibiotic power by preventing the formation of peptidoglycan cross-links in the bacterial cell wall. Other β-lactam antibiotics include the cephalosporins.
DESPITE THE success of producing penicillin by fermentation, chemists sought to synthesize penicillin. The goal was achieved in 1957 when John C. Sheehan, a chemistry professor at Massachusetts Institute of Technology and a former chemist at Merck, synthesized phenoxymethylpenicillin, also known as penicillin V. Sheehan also developed a method for converting 6-aminopenicillanic acid to penicillin.
A number of semisynthetic penicillin derivatives improving on the properties of penicillin have been developed since penicillin was first commercialized. Ampicillin, patented by Beecham in 1961, improved the oral absorption of penicillin. Amoxicillin, also patented by Beecham in 1964, further improved oral absorption. These compounds and other penicillin derivatives share the b-lactam nucleus but have different side chains.
Fleming, Florey, and Chain shared the Nobel Prize for Physiology or Medicine in 1945. In his Nobel lecture, Fleming was prescient and predicted what has indeed become a major problem: antibiotic resistance.
Fleming said: "The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and, by exposing his microbes to nonlethal quantities of the drug, make them resistant."
That has indeed been the case. Some bacteria produce an enzyme called β-lactamase that hydrolyzes and inactivates penicillin. Antibiotic resistance has increased as people take sublethal quantities of antibiotics and take antibiotics for viral infections, against which antibiotics are useless. One of the most feared infections acquired in hospitals today is methicillin-resistant Staphylococcus aureus. Efforts are under way to find new antibiotics that are effective against such drug-resistant bacteria.
◾ (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-[(phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
◾ Penicillin G
◾ benzylpenicillinic acid
1943, consortium of companies
Did you know that when penicillin was being developed during World War II, the British researchers rubbed penicillin mold spores into their clothing in case they had to destroy their research to keep it from the Germans?
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