Visit the Science History Institute and see this item on display in our permanent exhibition, Making Modernity. Introduced in by Gerhard Domagk — , sulfa drugs, or sulfonamides, all of which are related to the compound sulfanilamide, provided the first successful therapies for many bacterial diseases. As such, they proved to be the forerunners of antibiotics, showing that bacterial diseases are vulnerable to substances not natural to the human body.
Born the son of a teacher in Lagow, Germany, Domagk decided early in life to become a physician. His medical studies at the University of Kiel were interrupted by his service as a grenadier and medical corpsman in World War I. He completed his medical degree in and then began an academic career, pursuing research in pathology. He adopted a dynamic approach to pathology, incorporating physiology and chemistry into his work.
In this industrial setting Domagk felt at greater liberty to pursue his research and had far better resources at his command than in the university setting. Without making any tests, the "Elixer" was released, resulting in the deaths of people, mostly children, largely from kidney and liver failure. Massengill got off easy. Under U. To be called an elixir, ethanol had to be used. The tragedy did not stop sulfa drugs; the recognized benefits brought huge growth. In , U. By , more than an estimated 10 million lb was produced in the U.
A significant reason for the growth between and was the use of sulfa drugs in the war effort. American soldiers were taught to sprinkle sulfa powder immediately on any open wound to prevent infection.
To that end, every soldier was issued a first aid pack designed to be attached to his belt. In that pouch were a package of sulfa powder and a bandage to dress the wound. In addition, sulfa powder and sulfa tablets were main components of the combat medic's kit.
The story of sulfa drugs does not end with World War II, but it certainly slows down. They continued to be used for many bacterial infections well into the s, although by then they were getting competition from newer antibacterials, beginning with the enormous popularity of penicillin in the s.
Today their use is limited. The main use for sulfa drugs is as a treatment for urinary tract infections. Did you know that Gerhard Domagk's discovery brought honors for the researcher, including the Nobel Prize in Physiology or Medicine in ?
However, the Nazi regime in Germany would not allow him to travel to Stockholm to receive the honor. He did receive the medal in , but because of the time that had elapsed, he was not given the monetary award. Contact the reporter. Submit a Letter to the Editor for publication. Engage with us on Twitter. For further detail, see Williams [ 59 ]. The price decline as penicillin became a commodity chemical [ 8 ] resulted from the many improvements in the manufacturing methods.
The role of submerged fermentation and the use of corn steep liquor have already been discussed here. In fact, it was shown that addition of phenylacetic acid itself to fermentations increased penicillin yields in both surface and submerged cultures [ 47 ].
Many other precursors were subsequently identified [ 4 , 16 ]. One precursor, phenoxyacetic acid, gave rise to a clinically useful, new material, developed at Lilly Research Laboratories from , and termed penicillin V phenoxymethylpenicillin. Other precursors, e. Penicillin V is somewhat less active than benzylpenicillin but has the advantage that it can be used orally, being more stable to stomach acid. Another interesting development at Lilly was to form a salt of benzylpenicillin with the anesthetic, procaine.
This combination, procaine benzylpenicillin, reduces pain and discomfort associated with large intramuscular injections of benzylpenicillin itself.
Another major contribution was the selection and production of high-yielding fungal strains. In this connection, there was one further episode of serendipity in the penicillin story. It produced high penicillin yields in submerged cultures and was further improved by mutation X-ray or UV treatment.
So where did all of this leave the villain, Moyer? One writer states no source given that although Moyer was justified in claiming the British patents, his seniors were most annoyed by his actions.
Thus, finally, penicillin did come into the hands of industrial organizations and significant patent and monetary considerations came into play. Nonetheless, the glory days when penicillin was validated as a most valuable antibiotic and was produced in a small, improvised pilot plant, were in an academic environment Oxford University and the development was driven by a small group of dedicated amateurs.
At a later date when the cephalosporins were discovered and put to use, the Oxford workers had learned the lesson and patents were obtained. This cephalosporin work is not discussed here in order to keep this article to a reasonable length. Another discovery mode, a collaboration between a government research institute and a pharmaceutical company, was involved in the development of semi-synthetic penicillins. From early Chain [ 15 ] became involved with the UK Beecham group in this endeavor and also in the possible production of tartaric acid by a microbiological process.
These well-known pills, which were said to treat such complaints as bilious and nervous disorders, stomach wind and pain, headache, etc.
Heavily advertised, they became a household word in the UK and were available world-wide. This author remembers as a youngster, singing gleefully at Christmas-time, novel words to a familiar carol: Hark the herald angels sing,.
These pills had a very long run on the market, being in use for a century and a half; they were discontinued only in [ 2 ]. To reflect a growing diversity, the manufacturer of the famous pills had, by , become Beecham Pharmaceuticals Limited. By further chemical modification of the NH 2 group on the phenyl ring it was hoped to produce new penicillins resistant to penicillinase action.
A serendipitous observation, first made in Rome, was further explored at Brockham Park, beginning in , after Rolinson and Batchelor had returned to the UK. It was a simple finding with far-reaching results. When the fermentation broths producing p -aminobenzylpenicillin were assayed by a chemical method hydroxylamine reaction there was apparently a greater yield of antibiotic than indicated by a bioassay similar to that described by Heatley [ 15 ].
Surprisingly, the discrepancy was greatest when no precursor material was added to the fermentation. Meticulous work indicated that the difficulty was caused by the presence of 6-aminopenicillanic acid, 6-APA Fig.
Clark states that Chain compared this discovery with the finding of the activity of the sulfanilamide unit in Prontosil see earlier [ 15 ]. It is of interest that prior to this work at Beecham, a Japanese investigator, Koichi Kato, in had actually claimed the isolation of a penicillin nucleus incomplete penicillin from fermentations conducted without addition of phenylacetic acid [ 34 ]. The material was not well characterized e. Demain in [ 20 ]. The first penicillinase-resistant product formed from 6-APA was methicillin 2,6-dimethoxyphenylpenicillin.
Needless to say, 6-APA, methicillin, and the other semi-synthetic penicillins became the subjects of patents, the first application regarding 6-APA being filed on August 2, [ 60 ]. However, not all went smoothly with the Beecham patents. The case is very complex involving the disclosure of information and international law.
Very unpleasant legal difficulties accrued to Chain as a result of the 6-APA work with the Beecham group [ 15 ]. In several instances, serendipity played an important role.
It cannot be claimed that any one discovery mode was superior. However, all humanity can be grateful for the efforts of the four major players, all Nobel laureates——Chain, Domagk, Fleming, Florey—and appreciative of the fact that these antibiotics, in one way or another, were put in place.
A major distinction between the two discovery processes is that the sulfa drugs did not trigger any significant new technology for production. The manufacture of Prontosil, sulfapyridine, and other sulfa drugs, required the well-established technology of chemical engineering——adapting large-scale engineering methods to chemical synthesis of materials such as dyes and medicinals such as aspirin. Indeed, the production of Prontosil can be regarded as the manufacture of yet one more azo dye.
On the other hand, large-scale production of penicillin, beginning in the s, required major new technological accomplishments—development of large-capacity tanks with provision for agitation, maintenance of temperature, pH, and pure culture, and, above all, the requirement for large volumes of sterile oxygen air. That the levels of penicillin in the fermentation broths were modest and that penicillin is a relatively unstable molecule presented major challenges.
One major technological development was the development of large-scale freeze drying. All of this required the efforts not only of engineers but also of biologists. Increasingly, biotechnology has involved the application of genetics exemplified early on by the development of high-yielding strains, and more recently by studies of recombinant fungal strains. The work on penicillin has provided basic information on the enzymology of biosynthetic pathways for secondary metabolite production [ 21 ].
Thanks are also due to A. Demain for helpful comments after reading a draft of this paper. A reviewer is thanked for useful suggestions. Google Scholar. Behr A Food product and process of making same. US Patent , Biological precursors for benzylpenicillin penicillin G J Biol Chem Bentley R Holding a mirror to penicillin—a reflection Biochemist 13 Revisited Adv Appl Microbiol 52 Reflections on the production of commodity chemicals by microorganisms Adv Appl Microbiol 63 1 32 Google Preview.
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Macfarlane RG Howard Florey. The making of a great scientist Oxford Oxford University Press. Moyer AJ Method for production of penicillin. Moyer AJ Improvements in or relating to methods for producing penicillin. British Patent , Production of penicillin in surface cultures J Bacteriol 51 57 The effect of phenylacetic acid on penicillin production J Bacteriol 53 Improved process Ind Eng Chem 32 Methods of assay J Bacteriol 47 Bacterial production Ind Eng Chem 32 During the 19th century doctors discovered that many diseases are caused by infections - attacks by microorganisms.
This led to the search for chemical preparations to combat bacteria and other microorganisms. The challenge was long thought to be impossible, but in Gerhard Domagk and his colleagues demonstrated in mice experiments that sulfonamides could be used to counteract bacteria that cause blood poisoning.
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