Prontosil
Encyclopedia
Prontosil, the first commercially available antibacterial antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

 (with a relatively broad effect against Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...

 cocci
Coccus
Coccus can be used to describe any bacterium that has a spherical shape. It is one of the three distinct types of bacteria shapes, the other two being bacillus and spirillum cells...

 but not against enterobacteria
Enterobacteriaceae
The Enterobacteriaceae is a large family of bacteria that includes many of the more familiar pathogens, such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella and Shigella. This family is the only representative in the order Enterobacteriales of the class Gammaproteobacteria in the...

), was developed by a research team at the Bayer
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...

 Laboratories of the IG Farben
IG Farben
I.G. Farbenindustrie AG was a German chemical industry conglomerate. Its name is taken from Interessen-Gemeinschaft Farbenindustrie AG . The company was formed in 1925 from a number of major companies that had been working together closely since World War I...

 conglomerate in Germany. The discovery and development of this first sulfonamide
Sulfonamide (medicine)
Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame...

 drug opened a new era in medicine.

History

Sulfonamidochrysoidine was first synthesized by Bayer chemists Josef Klarer and Fritz Mietzsch as part of a research program designed to find dyes that might act as antibacterial drugs in the body. The molecule was tested and found effective in the late autumn of 1932 against some important bacterial infections in mice by Gerhard Domagk
Gerhard Domagk
Gerhard Johannes Paul Domagk was a German pathologist and bacteriologist credited with the discovery of Sulfonamidochrysoidine – the first commercially available antibiotic – for which he received the 1939 Nobel Prize in Physiology or Medicine.Domagk was born in Lagow, Brandenburg, the...

, who subsequently received the 1939 Nobel Prize in Medicine. Prontosil was the result of five years of testing involving thousands of compounds related to azo dyes.

The crucial test result (in a murine model of Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes is a spherical, Gram-positive bacterium that is the cause of group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S...

systemic infection) that preliminarily established the antibacterial efficacy of Prontosil in mice dates from late December 1931. IG Farben filed a German patent application concerning its medical utility on December 25, 1932. The synthesis of the compound had been first reported by Paul Gelmo, a chemistry student working at the University of Vienna
University of Vienna
The University of Vienna is a public university located in Vienna, Austria. It was founded by Duke Rudolph IV in 1365 and is the oldest university in the German-speaking world...

 in his 1909 thesis, although he had not realized its medical potential.

The readily water-soluble sodium salt of sulfonamidochrysoidine, which gives a burgundy red solution and was trademarked Prontosil Solubile, was clinically investigated between 1932 and 1934, first at the nearby hospital at Wuppertal
Wuppertal
Wuppertal is a city in North Rhine-Westphalia, Germany. It is located in and around the Wupper river valley, and is situated east of the city of Düsseldorf and south of the Ruhr area. With a population of approximately 350,000, it is the largest city in the Bergisches Land...

-Elberfeld headed by Philipp Klee, and then at the Düsseldorf university
Heinrich Heine University of Düsseldorf
Heinrich Heine University , located in Düsseldorf, Germany, is named after German poet and political thinker Heinrich Heine, who was born in Düsseldorf in 1797. It became a full-fledged university in 1965 and currently comprises faculties of law, medicine, philosophy, mathematics and natural...

 hospital. The results were published in a series of articles in the February 15, 1935 issue of Germany's then pre-eminent medical scientific journal, Deutsche Medizinische Wochenschrift, and were initially received with some skepticism by a medical community bent on vaccination and crude immunotherapy.

Then Leonard Colebrook
Leonard Colebrook
Leonard Colebrook FRS was an English physician and Bacteriologistwho in 1935 showed Prontosil was effective against haemolytic streptococcus in childbirthand hence a cure for puerperal fever...

 introduced it as a cure for puerperal fever
Puerperal fever
Puerperal fever or childbed fever, is a bacterial infection contracted by women during childbirth or miscarriage. It can develop into puerperal sepsis, which is a serious form of septicaemia. If untreated, it is often fatal....

. As impressive clinical successes with Prontosil started to be reported from all over Europe, and especially after the widely published treatment of Franklin Delano Roosevelt, Jr.
Franklin Delano Roosevelt, Jr.
Franklin Delano Roosevelt, Jr. was an American politician. He was the fifth child of U.S. President Franklin D. Roosevelt, Sr. and his wife Eleanor.-Personal life:...

 (a son of U.S. president Franklin D. Roosevelt
Franklin D. Roosevelt
Franklin Delano Roosevelt , also known by his initials, FDR, was the 32nd President of the United States and a central figure in world events during the mid-20th century, leading the United States during a time of worldwide economic crisis and world war...

), acceptance was quick and dozens of medicinal chemistry teams set out to improve on Prontosil. (Eleanor Bliss and Perrin Long from Johns Hopkins introduced the drug to the United States.)

Eclipse and legacy

Working in the laboratory of Ernest Fourneau
Ernest Fourneau
Ernest Fourneau was a French medicinal chemist, who played a major role in the discovery of synthetic local anesthetics, as well as in the synthesis of suramin...

, Jacques and Thérèse Tréfouël, Daniel Bovet
Daniel Bovet
Daniel Bovet was a Swiss-born Italian pharmacologist who won the 1957 Nobel Prize in Physiology or Medicine for his discovery of drugs that block the actions of specific neurotransmitters. He is best known for his discovery in 1937 of antihistamines, which block the neurotransmitter histamine and...

 and Federico Nitti at the Pasteur Institute
Pasteur Institute
The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who made some of the greatest breakthroughs in modern medicine at the time, including pasteurization and vaccines for anthrax...

 in Paris accidentally discovered at the end of 1935 that Prontosil is metabolized to sulfanilamide (para-aminobenzenesulfonamide), a much simpler, colorless molecule, redefining Prontosil as a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...

. Prontylin became the first oral version of sulfanilamide by Bayer, which had actually obtained a German patent on sulfanilamide as early as 1909, without realizing its medical potential at this time.

It has been argued that IG Farben might have made its breakthrough discovery with sulfanilamide in 1932 but, recognizing that it would not be patentable as an antibiotic, had spent the next three years developing Prontosil as new, and therefore more easily patentable, compound. However Daniel Bovet, Nobel Prize of medicine and one of the authors of the French discovery, wrote in 1988: "Today, we have the proof that the chemists of Elberfeld were unaware of the properties of sulfanilamide at the time of our discovery and that it was by our communication that they were informed. To be convinced about it, it is enough to attentively examine the monthly reports of work of Mietzsch and Klarer during years 1935-1936 and especially the Log Book of G. Domagk: the formula of sulphamide is consigned there - without comment - not before January 1936."

Sulfanilamide was cheap to produce and (due to the early date of its original composition of matter patent which made no reference to a medical use) was already off-patent when its antibiotic properties were first made public. Since the sulfanilamide moiety was also easy to link into other molecules, chemists soon gave rise to hundreds of second-generation sulfonamide drugs. As a result, Prontosil failed to make the profits in the marketplace hoped for by Bayer. Although quickly eclipsed by these newer "sulfa drugs" and, in the mid-1940s and through the 1950s by penicillin and other antibiotics that proved more effective against more types of bacteria, Prontosil remained on the market until the 1960s. Prontosil's discovery ushered in the era of antibiotics and had a profound impact on pharmaceutical research, drug laws, and medical history.

Sulfonamide-trimethoprim
Trimethoprim
Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections.It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors...

 combinations (Co-trimoxazole
Co-trimoxazole
Trimethoprim/sulfamethoxazole or co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections.The name co-trimoxazole is the British Approved Name, and has been marketed worldwide...

) are still used extensively for opportunistic infections in patients with AIDS, urinary infections and burn therapy. However, many other uses of sulfa drugs have been largely replaced by beta-lactam
Beta-lactam
A β-lactam ring, is a four-membered lactam. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl...

antibiotics.
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