Prontosil, the first commercially available antibacterial
antibioticIn common usage, an antibiotic is a substance or compound that kills or inhibits the growth of bacteria...
(with a relatively broad effect against
Gram-positiveGram-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...
cocciCocci are any micorganism whose overall shape is spherical or nearly spherical. Describing a bacterium as a coccus, or sphere, distinguishes it from bacillus, or rod...
but not against
enterobacteriaThe Enterobacteriaceae are a large family of bacteria, including many of the more familiar pathogens, such as Salmonella and Escherichia coli...
), was developed by a research team at the
BayerBayer AG is a German chemical and pharmaceutical company founded in Barmen, Germany in 1863. Today it is headquartered in Leverkusen, North Rhine-Westphalia, Germany. It is well-known for its original brand of aspirin...
Laboratories of the
IG FarbenI.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
sulfonamideThere are several sulfonamide-based 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.
Sulfonamidochrysoidine (KI-730), first synthesized by Bayer chemists Josef Klarer and Fritz Mietzsch, was tested and found effective against some important bacterial infections in mice by
Gerhard DomagkGerhard Johannes Paul Domagk was a German pathologist and bacteriologist credited with the discovery of Sulfonamidochrysoidine – the first commercially available antibacterial antibiotic – for which he received the 1939 Nobel Prize in Physiology or Medicine.Domagk was born in Lagow,...
, who subsequently received the 1939 Nobel Prize in Medicine.
Prontosil, the first commercially available antibacterial
antibioticIn common usage, an antibiotic is a substance or compound that kills or inhibits the growth of bacteria...
(with a relatively broad effect against
Gram-positiveGram-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...
cocciCocci are any micorganism whose overall shape is spherical or nearly spherical. Describing a bacterium as a coccus, or sphere, distinguishes it from bacillus, or rod...
but not against
enterobacteriaThe Enterobacteriaceae are a large family of bacteria, including many of the more familiar pathogens, such as Salmonella and Escherichia coli...
), was developed by a research team at the
BayerBayer AG is a German chemical and pharmaceutical company founded in Barmen, Germany in 1863. Today it is headquartered in Leverkusen, North Rhine-Westphalia, Germany. It is well-known for its original brand of aspirin...
Laboratories of the
IG FarbenI.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
sulfonamideThere are several sulfonamide-based 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 (KI-730), first synthesized by Bayer chemists Josef Klarer and Fritz Mietzsch, was tested and found effective against some important bacterial infections in mice by
Gerhard DomagkGerhard Johannes Paul Domagk was a German pathologist and bacteriologist credited with the discovery of Sulfonamidochrysoidine – the first commercially available antibacterial antibiotic – for which he received the 1939 Nobel Prize in Physiology or Medicine.Domagk was born in Lagow,...
, who subsequently received the 1939 Nobel Prize in Medicine. Prontosil was the result of five years of research and testing involving thousands of compounds related to azo dyes.
Leonard ColebrookLeonard 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 feverPuerperal fever , also called childbed fever, can develop into puerperal sepsis, which is a serious form of septicaemia contracted by a woman during or shortly after childbirth, miscarriage or abortion. If untreated, it is life-threatening.The most common infection causing puerperal fever...
.
The crucial test result (in a murine model of
Streptococcus pyogenesStreptococcus pyogenes is a spherical gram-positive bacterium that grows in long chains and 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. 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 is a city in North Rhine-Westphalia, Germany. It is located on the Wupper river south of the Ruhr area. Population 361,333 ....
-Elberfeld headed by Philipp Klee, and then at the
Düsseldorf universityThe Heinrich Heine University of Düsseldorf is a university in Düsseldorf, Germany. It is named after the German poet and political thinker Heinrich Heine, who was born in Düsseldorf in 1797. Since 1965 it has been a fully-fledged university, consisting today of faculties of law, medicine,...
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.
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. was the fifth child of Anna Eleanor Roosevelt and Franklin D. Roosevelt .-Personal life:...
(a son of U.S. president
Franklin D. RooseveltFranklin Delano Roosevelt , the only U.S. President elected to more than two terms, was 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.
Eclipse and legacy
Jacques and Thérèse Trefouel and their team at the French
Pasteur InstituteThe 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, its founder and first director, who had successfully developed the first antirabies serum in 1885...
found in 1936 that prontosil is metabolized to sulfanilamide (para-aminophenylsulfonamide), a much simpler, colorless molecule, redefining Prontosil as a
prodrugA prodrug is a pharmacological substance that is administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and excretion optimization...
.
Sulfanilamide was already off patent (it had first been synthesized by Paul Gelmo, a chemistry student working at the
University of ViennaThe University of Vienna is a public university located in Vienna, Austria. It was founded by Duke Rudolph IV in 1365 and is, therefore, the oldest university in the German-speaking world and one of the largest in Central Europe.-History:...
in his 1909 thesis who however had not realized its medical potential) and cheap to produce. The sulfanilamide moiety was also easy to link into other molecules, and 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, penicillin and a string of newer 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 combinations are used extensively for opportunistic infections in patients with AIDS, urinary infections and burn therapy. However their uses are greatly replaced by
beta-lactam||-||-||-||-||-||-||}A beta-lactam ring is a lactam with a heteroatomic ring structure, consisting of three carbon atoms and one nitrogen atom...
antibiotics.