In the days when there were no antibiotics, it was difficult for humans to win the battle against diseases because death always came before cure. However, the development of human medicine has never stopped.
In times of war when diseases were rampant and medical care was backward, if one was unfortunate enough to be infected by bacteria, the odds were that it would also mean death. There was a German pathologist named Gerhard Dumak, who had witnessed many similar cases. One of the closest patients was his daughter, who was only three years old.
In 1932, during an injection, his daughter was severely infected by an unsterilized needle and streptococcus bacteria invaded her body. The wound then began to become inflamed and worsened, and his young daughter had a constant high fever. At the time, penicillin had just been discovered and was not yet developed enough to be used in clinical treatment.
The treating doctor told Dumak that to save his daughter’s life, she would have to undergo amputation of her hand, which was inflamed and swollen from the streptococcus infection.
Gerhard Dumak
Seeing his daughter’s critical condition and not wanting to let her amputate her hand at such a young age, could Dumak, who also belongs to the medical field, do anything? In fact, the project he was working on at the time happened to be about a bacterial infection.
He was working at the Bayer laboratory of Farben, which was the largest chemical company in Europe at the time. Dumak’s job, however, was to find substances with antibacterial properties from dyes to develop antibacterial drugs.
Dyes can also cure diseases? And there was a lab that specialized in how to use dyes to cure diseases? Yes, that’s what Bayer’s lab was doing at the time. The two founders, one a businessman and the other a master pigment maker, and medicine are not the same. Later, the company switched to the direction of medical and pharmaceutical products, which also depended on a surprise discovery.
In 1856, a scientist discovered that a purple dye could penetrate the shell of bacteria and make them purple. Further experiments led to the discovery that some synthetic dyes could inhibit the growth of bacteria. In 1925, Bayer merged with other companies to form Farben, which became a chemical and pharmaceutical company.
As one of the researchers, Dumasque had already tried thousands of dyes, but all had failed. This was when his daughter’s sudden and critical illness added to the pressure of his work, and he couldn’t wait to find an effective antibacterial drug.
Sometimes luck comes at the right time, when hope is possible in a desperate situation.
Before that, Dumasque had been experimenting on mice for three years and had tested thousands of azo* dyes. He first infected the mice with germs and then fed or injected them with drugs to test their reaction to the drugs. But he could only witness a batch of mice infested with the germs and died.
It was not until he tested a red dye called Paramount, which contains a sulfa-like substance that does not show antibacterial activity in vitro, but surprisingly showed antibacterial effects when it entered the mice.
This is an intermediate of a synthetic dye. Sulforaphane was first synthesized by humans as early as 1908 and has been used in the dye industry since then. But to uncover the antibacterial effect of sulfonamide, Dumak is still the first person. After so many discouraging failures, Dumak finally discovered a dye with antibacterial properties.
*Note: Azo compounds are a class of organic compounds containing azo groups, and “N=N” is called azo group.
The red dye Bironomide
However, this drug has only been tested on mice and rabbits, and the tolerance level of this type of mammal to Bironomide is about 500mg/kg body weight or less, and if the dose is increased, it will cause abnormal effects such as vomiting.
Even if sulfonamides are found to have antibacterial effects in animals, do they have the same effect in humans? What dose should be chosen? Everything is still unknown.
This was an important stage in the clinical trials of the drug, and a critical time for Dumak’s daughter to receive urgent medical treatment. So Dumak decided to give his daughter the chance to avoid amputation from this risk – and his 3-year-old daughter became the first clinical trial participant of Parlodoxin.
Dumak attempted to give his daughter several doses of Parlodoxin, with doses documented to be probably more than 10 grams, a dose several times the standard modern dose. However, there was also a miraculous effect of vigorous medical effort. After a few days, his daughter’s condition gradually improved, and it seemed that the infected bacteria had indeed been effectively suppressed, and the arm that was supposed to be amputated was saved.
In 1935, he published the results of his animal and human studies and announced the discovery of the first synthetic antibacterial drug to the world.
Red blood cells infected with staphylococcus (left) and streptococcus (right)
The reason why Bironomide, a sulfonamide drug, stands out from the crowd of dyes is actually a game of civeting on a microscopic level.
Bacteria are usually inseparable from the presence of folic acid, which is necessary for the synthesis of nucleic acids and for the growth and reproduction of bacteria. Para-aminobenzoic acid (PABA) is the raw material for the synthesis of folic acid in bacteria, and is also the starting point for the action of sulfonamide.
Once the sulfa drug enters the body, it begins to compete with PABA for dihydrofolate synthase in bacteria. Once the sulfonamides compete successfully and bind to dihydrofolate, the bacteria are also unable to use PABA to synthesize folic acid properly. Without this important substance, bacteria can no longer synthesize proteins and nucleic acids, and the drug thus exerts its antibacterial effect of preventing bacterial growth and reproduction.
Although the news that Dumak had synthesized an antibacterial drug from an industrial dye was sensational, the conservative medical community at the time was mostly afraid to use the new drug until the son of the President of the United States personally endorsed Parlodip.
Just a year after the research paper was published, the son of U.S. President Franklin D. Roosevelt also developed streptococcal laryngitis. At that time, even after consulting the elite of Harvard Medical School, the answer was only death. This is when a doctor heard that a new drug had come out of Germany and gave young Franklin a try with the psychology of a dead horse, and he was really cured.
This naturally aroused the attention of the American public and even the people of the world, so Bailang Doxi was widely reported by the media, from the fame, people also began to use this new drug with antibacterial effect.
At the same time, however, many pharmaceutical companies also began to compete to develop sulfa drugs. Within a decade, more than 5,000 sulfonamide derivatives had been developed and synthesized. However, behind the rapid commercialization of drugs in a frenzy of profit-seeking manufacturers, there were also terrible drug accidents.
One pharmaceutical company had the whim to dissolve a solid drug into a liquid drug with a sweet taste, but chose the wrong solvent, which eventually caused more than 100 deaths in the Sulfanilamide Elixir incident. Among the more than 5,000 kinds of related drugs at that time, there were only about 20 kinds with real medical value.
Bironomide was the first commercially available antimicrobial drug synthesized by man, a great achievement that undoubtedly deserved to be awarded the Nobel Prize, which Dumasco received in 1939 for physiology or medicine, but which he was unable to accept.
Two years prior to this, Hitler and the Nazi Party issued a rule forbidding German citizens from accepting the Nobel Prize. This was because in 1935, the Nobel Committee awarded the Nobel Peace Prize to an anti-fascist German journalist – Karl von Ousietzky – which completely angered the German authorities.
So Dumak was limited by the country’s situation and did not get the medal himself until 1947, but the Nobel Prize money had long been divided up.
Today, sulfa drugs have been largely replaced by antibiotics or quinolones, and sulfa drugs are rarely prescribed separately in the prescriptions of developed countries. In developing countries, however, it is still widely used to treat bacterial infections such as trachoma and urinary tract infections.
With the development of medical technology, many drugs that affect the fate of mankind will gradually disappear from our view. But these histories have their own unique value and significance, and should make people remember the people who suffered from the ravages of bacterial infections and diseases in the old days, as well as the persistence and luck of Dumac.
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