Until the beginning of the 20th century, the treatment of infections was based mainly on folklore, stereotypes and superstitions. The history of the discovery of antibiotics in this regard is very interesting. Mixtures with antimicrobial properties used in the treatment of infections have been described over 2,000 years ago. Many ancient cultures, including the ancient Egyptians and ancient Greeks, used specially selected mold, plant materials, and extracts to treat infections.
Their use in modern medicine began with the discovery of synthetic antibiotics obtained from dyes. Usually, with the mention of this fact, any history of the discovery of antibiotics begins.
First research
Synthetic antibacterial chemotherapy as a science and the development of antibacterial drugs began in Germany with studies conducted by Paul Erlich in the late 1880s. Ehrlich noted that some dyes will stain human, animal or bacterial cells, while others will not. He then proposed the idea of creating chemicals that would act as a selective drug that would bind and kill bacteria without harming the human body. After screening hundreds of dyes against various organisms in 1907, he discovered a medicinally useful substance, the first synthetic antibacterial drug, now called arsphenamine. You will receive other information about the history of the discovery of antibiotics later in the article.
German-Japanese Union
The era of antibiotic treatment began with the discovery of synthetic antibiotics derived from arsenic by Alfred Bertheim and Erlich in 1907. Erlich and Bertheim experimented with various dye-derived chemicals to treat trypanosomiasis in mice and spirochete infections in rabbits. While their early compounds were too toxic, Erlich and Sahachiro Hata, the Japanese bacteriologist working with the first to find a cure for syphilis, achieved success in their 606th attempt from a series of complex experiments.
Recognition and commercial success
In 1910, Erlich and Hut announced their discovery, which they called “606,” at the Congress of Internal Medicine in Wiesbaden. Hoechst began selling the complex by the end of 1910 under the name Salvarsan. This drug is now known as arsphenamine. The drug was used to treat syphilis in the first half of the 20th century. In 1908, Erlich received the Nobel Prize in Physiology or Medicine for his contribution to immunology. The hut was nominated for the Nobel Prize in Chemistry in 1911 and the Nobel Prize in Physiology or Medicine in 1912 and 1913.
A new era in the history of medicine
The first sulfonamide and the first systemically active antibacterial drug, Pontosil, was developed by a research team led by Gerhard Domagk in 1932 or 1933 at the Bayer laboratories of the IG Farben conglomerate in Germany, for which Domagk received the 1939 Nobel Prize in Physiology or Medicine. Sulfanilamide (the active component of Prontosil) was not patentable because it had already been used in the dye industry for several years. Prontosyl had a relatively broad effect against gram-positive cocci, but not against enterobacteria. His success in treatment was usually financially stimulated by the human body and its immunity. The discovery and development of this sulfonamide preparation marked the era of antibacterial drugs.
Penicillin antibiotic discovery
The history of penicillin follows a series of observations and discoveries of obvious evidence of antibiotic activity in mold, preceding the synthesis of chemical penicillin in 1928. In ancient societies, there are examples of the use of wood molds to treat infections. However, it is not known whether these molds were penicillin species. Scottish doctor Alexander Fleming was the first to suggest that Penicillium mold should secrete an antibacterial substance, which he called penicillin in 1928. Penicillin was the first modern antibiotic.
Further study of mold
But information on the history of the discovery of antibiotics is not limited to the 20 years of the last century. Over the next twelve years, Fleming grew, distributed, and studied interesting mold, which was recognized as a rare species of Penicillium notatum (now Penicillium chrysogenum). Many later scientists were involved in the stabilization and mass production of penicillin and in search of more productive Penicillium strains. The list of these scientists includes Ernst Chain, Howard Flory, Norman Heatley and Edward Abraham. Soon after the discovery of penicillin, scientists discovered that some pathogenic pathogens show antibiotic resistance to penicillin. Research aimed at developing more effective strains and studying the causes and mechanisms of antibiotic resistance continues today.
The wisdom of the ancients
Many ancient cultures, including those in Egypt, Greece and India, independently discovered the beneficial properties of mushrooms and plants in the treatment of infection. These procedures often worked because many organisms, including many molds, naturally produce antibiotic substances. However, the ancient healers could not accurately identify or isolate the active components of these organisms. In Sri Lanka in the second century BC. e. soldiers in the army of King Dutugemunu (161-137 BC) checked that buttercakes (traditional Sri Lankan sweets) were stored in their hearths for a long time before embarking on military campaigns to prepare complementary foods from moldy cakes to treat wounds .
In 17th-century Poland, wet bread was mixed with cobwebs (which often contained spores of fungi) to treat wounds. The technique was mentioned by Henryk Sienkevich in his 1884 book “With Fire and Sword”. In England, in 1640, the idea of using mold as a form of treatment was documented by pharmacists such as John Parkinson, the duke of the king, who advocated the use of mold in his book on pharmacology. Alexander Fleming's discovery of mold-based antibiotics will turn the world around.
New time
The modern history of penicillin research begins in earnest in the 1870s in the United Kingdom. Sir John Scott Bourdon-Sanderson, who went to St. Mary’s Hospital (1852-1858) and then worked there as a lecturer (1854-1862), noticed that moldy culture fluid interferes with the growth and reproduction of bacteria. The discovery of Bourdon-Sanderson prompted Joseph Lister, an English surgeon and father of modern antiseptics, to discover in 1871 that urine specimens infected with mold produce the same effect. Lister also described the antibacterial effect on human tissue of a type of mold, which he called Penicillium glaucum. Strictly speaking, 1871 can be called the date of discovery of antibiotics. But only formally. These antibiotics suitable for continuous use and production will be produced much later.
In 1874, the Welsh physician William Roberts, who later coined the term “enzyme,” observed that bacterial contamination was usually absent in Penicillium glaucum laboratory cultures. John Tyndall continued the work of Bourdon-Sanderson and demonstrated to the Royal Society in 1875 the antibacterial action of the fungus Penicillium. By this time, Bacillus anthracis was shown to cause anthrax, which was the first demonstration that a particular bacterium caused a specific disease. In 1877, French biologists Luis Pasteur and Jules Francois Joubert noted that anthrax bacilli cultures, when they are contaminated with mold, can be successfully destroyed. Some references suggest that Pasteur identified the strain of mold he used as penicillium notatum. However, Paul de Cruyff's 1926 Microbial Hunters book describes the incident as contamination with other bacteria, rather than mold. In 1887, Garre got similar results. In 1895, Vincenzo Tiberio, an Italian doctor from the University of Naples, published a study on mold in a reservoir in Arzano, which showed antibacterial properties. All this must be known, since in any textbook of pharmacology the history of the discovery of antibiotics has a special place.
Two years later, Ernest Duchenne, at the School du Sant Militière in Lyon, independently discovered the healing properties of Penicillium plexiglass mold, successfully curing infected guinea pigs from typhoid fever. He published his dissertation in 1897, but it was ignored by the Pasteur Institute. Duchenne himself used the discovery made earlier by Arab nomads who used mold spores to treat horse ulcers. Duchenne did not claim that mold contains any antibacterial substance, only that mold protects animals in some way. Penicillin secreted by Fleming does not cure typhoid fever, and therefore it remains unknown which substance may be responsible for the cure of Duchenne guinea pigs.
Other mold observations
The history of the discovery of antibiotics is not limited to this. In Belgium in 1920, Andre Grazia and Sarah Dan observed fungal infection in one of their cultures, Staphylococcus aureus, which prevented the growth of bacteria. They identified the fungus as a type of penicillium and presented their observations in the form of a laboratory protocol, which received little attention. Costa Rican scientist researcher Picado Twight also noted the antibiotic effect of Penicillium in 1923. In the history of pharmacology, the discovery of antibiotics has played a huge role.
Great breakthrough
In 1928, Scottish biologist Alexander Fleming noticed a halo of inhibition of bacterial growth in a culture of Staphylococcus rods. He concluded that mold releases a substance that inhibits the growth of bacteria. He grew a pure mold culture and subsequently synthesized what he later called "penicillin." Over the next twelve years, Fleming grew and selected the original strain of mold, which was ultimately identified as penicillium notaum (today - Penicillium chrysogenum). He failed to create a stable form for mass production. Nevertheless, Fleming's discovery of antibiotics marked the beginning of a new era in the history of medicine.
Continuation of the great work
Cecil George Payne, a pathologist at the Royal Infirmary in Sheffield, tried to treat penicillin for sycosis (eruptions in the follicle), but his experiment was unsuccessful, probably because the drug did not penetrate deep enough. Turning to the treatment of neonatal ophthalmia, gonococcal infection in infants, he achieved the first successful healing on November 25, 1930. He cured four patients (one adult and three babies) of eye infections, although the fifth patient was unlucky.
At Oxford, Howard Walter Flory organized a large and very experienced group for biochemical research, including Ernst Boris Zein and Norman Heatley, to conduct clinical trials and produce stable penicillin in the required quantity. In 1940, Zein and Edward Abraham reported the first sign of antibiotic resistance to penicillin, a strain of E. coli that produced the penicillinase enzyme, which can destroy penicillin and completely deny its antibacterial effect.
Industrial production
Between 1941 and 1943, Moyer, Coghill, and Raper, at the US Department of Agriculture's North Regional Research Laboratory (PMR) in Peoria, Illinois, USA, developed methods for the industrial production of penicillin and isolated high-yielding strains of Penicillium fungus. In December 1942, the victims of the fire at Coconut Grove in Boston were the first burn patients to be successfully treated with penicillin. A simultaneous study by Jasper H. Kane and other Pfizer scientists in Brooklyn developed a practical deep fermentation method for producing large quantities of pharmaceutical grade penicillin.
The discovery of antibiotics in Russia occurred just after the introduction of penicillin in the USSR in the late 1930s, when Ermolyeva was engaged in their study. The role of Russia in this story, although somewhat secondary, is also important. It is not in vain that when they talk about the discovery of antibiotics, Fleming, Cheyne, Flory, Ermolyev are the main names mentioned by medical historians.
Chemists get involved
Dorothy Hodgkin determined the correct chemical structure of penicillin using x-ray crystallography at Oxford in 1945. In 1952, in Kundle, Tyrol, Austria, Hans Margreiter and Ernst Brandl of the University of Biochemistry (now Sandoz) developed the first acid-resistant penicillin for oral administration, penicillin B. The American chemist John S. Sheehan of the Massachusetts Institute of Technology (MIT) subsequently completed The first chemical synthesis of penicillin in 1957. The reader must have realized that the discovery of antibiotics in microbiology lasted almost half the last century. In the United Kingdom, second-generation semi-synthetic β-lactam methicillin was introduced in the United Kingdom to combat first-generation resistant penicillinases in 1959. Probably, at present there are forms of staphylococci resistant to methicillin. It is worth noting that among the discoveries of the 20th century, antibiotics occupy a very honorable place.
Antibiotic bacteria
Observations of the growth of certain microorganisms that inhibit the growth of other bacteria have been observed since the late 19th century. These observations of the synthesis of antibiotics between microorganisms have led to the discovery of natural antibacterial agents. Louis Pasteur remarked: “If we could interfere with the antagonism observed between some bacteria, this would bring perhaps the greatest hope for therapy.” This was a kind of turning point in the history of the discovery of antibiotics.
A little more about the 19th century
In 1874, physician Sir William Roberts noted that Penicillium glaucum mold cultures, which are used in the manufacture of certain types of blue cheese, do not exhibit bacterial contamination. In 1876, physicist John Tyndall also contributed to this area. Pasteur conducted a study showing that Bacillus anthracis would not grow in the presence of Penicillium notatum bound mold.
In 1895, an Italian doctor, Vincenzo Tiberio, published an article on the antibacterial power of certain mold extracts.
In 1897, doctoral student Ernest Duchenne wrote the work "Contribution to the elimination of microorganisms: antagonism, antagonistic thinking and pathogens." This was the first known scientific study of the therapeutic possibilities of mold as a result of their antimicrobial activity. In his work, Duchenne suggested that bacteria and mold take part in the eternal battle for survival. Duchesen observed that E. coli was removed with Penicillium glaucum when they both grew in the same culture. He also noticed that when he inoculated laboratory animals with lethal doses of typhoid bacilli along with Penicillium glaucum, the animals did not die from typhoid fever. Unfortunately, Duchenne’s military service after receiving a degree did not allow him to conduct further research. Duchenne died of tuberculosis, a disease that is now being treated with antibiotics.
And only Fleming, after more than 30 years, suggested that mold should secrete an antibacterial substance, which he called penicillin in 1928. The duet that determined the history of the discovery of antibiotics is Fleming / Waxman. Fleming believed that its antibacterial properties could be used for chemotherapy. Initially, he characterized some of its biological properties and tried to use a crude drug to treat certain infections, but could not continue its development without the help of trained chemists. Nobody played such a decisive role in this epic as the scientific duet Fleming / Waxman, the history of the discovery of antibiotics will not forget them.
But there were other important names in this epic. As mentioned earlier, chemists managed to clean penicillin only in 1942, but until 1945 it became widely available outside the allied military. Norman Heatley later developed a back extraction technique to efficiently clean bulk penicillin. The chemical structure of penicillin was first proposed by Abraham in 1942, and then later confirmed by Dorothy Crowfoot Hodgkin in 1945. Purified penicillin showed strong antibacterial activity against a wide range of bacteria and had low toxicity in humans. In addition, its activity was not inhibited by biological components such as pus, unlike synthetic sulfonamides. The development of penicillin potential has led to a renewed interest in the search for antibiotic compounds with similar efficacy and safety. Zein and Flory shared the 1945 Nobel Prize in medicine with Fleming, who discovered this wonderful mold. The discovery of Ermolyeva's antibiotics was expectedly ignored by the Western scientific community.
Other mold-based antibiotics
Flory attributed to Rene Dubot an innovative approach to the deliberate and systematic search for antibacterial compounds, which led to the discovery of gramicidin and revived Flory's research in the field of penicillin properties. In 1939, with the outbreak of World War II, Dubot announced the discovery of the first naturally-derived antibiotic, thyrotricin. It was one of the first commercial antibiotics that was very effective in treating wounds and ulcers during World War II. However, gramicidin could not be used systemically due to toxicity. Thyrocidine has also proven to be too toxic for systemic use. The research results obtained during this period were not divided between the axis and the allied powers during the Second World War and were in limited demand in the world during the Cold War. The presentation of the discovery of antibiotics took place mainly in developed countries of the West.
Name history
The term “antibiotic”, meaning “against life,” was coined by the French bacteriologist Jean-Paul Wilkemin as a descriptive name for the property exhibited by these early antibacterial drugs. The antibiotic was first described in 1877 when Louis Pasteur and Robert Koch watched a bacillus die under the influence of Bacillus anthracis. These drugs were later renamed antibiotics by Selman Waxman, an American microbiologist, in 1942. This date should be included in the list of antibiotic discovery years.
The term “antibiotic” was first used in 1942 by Selman Waxman and his collaborators in journal articles to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms. This definition excluded substances that kill bacteria but are not produced by microorganisms (such as gastric juices and hydrogen peroxide). He also ruled out synthetic antibacterial compounds such as sulfonamides. When used currently, the term “antibiotic” is applied to any drug that kills bacteria or inhibits their growth, regardless of whether the drug is produced by a microorganism or not.
Etymology
The term “antibiotic” comes from the prefix “anti” and the Greek word βιωτικός (biōtikos), “liveable, living”, which comes from βίωσις (biōsis), “lifestyle”, as well as the root βίος (bios) “life”. The term “antibacterial” comes from the Greek ἀντί (anti), “against” + βακτήριον (baktērion), a diminutive of βακτηρία (baktēria), “reed”, since the first bacteria found were rod-shaped in shape.
Alternatives to antibiotics
An increase in the number of bacterial strains that are resistant to traditional antibiotic therapies along with a decrease in the number of new antibiotics that are currently being developed as drugs has prompted the development of strategies for treating bacterial diseases that are an alternative to traditional antibacterial drugs. Non-specific approaches (that is, products other than classical antibacterial agents) that target bacteria or approaches that target the host, including phage therapy and vaccines, are also being investigated to combat this problem.
Vaccines
Vaccines rely on immune modulation or augmentation. Vaccination either excites or strengthens a person’s immunity to prevent infection, leading to macrophage activation, antibody production, inflammation, and other classic immune responses. Antibacterial vaccines are responsible for a sharp reduction in global bacterial diseases. Vaccines obtained from attenuated whole cells or lysates have been replaced mainly by less reactive, cell-free vaccines consisting of purified components, including capsular polysaccharides and their conjugates, by protein carriers, as well as inactivated toxins (toxoids) and proteins.
Phage therapy
Phagotherapy is another treatment for antibiotic-resistant strains of bacteria. Phage therapy infects pathogenic bacteria with its own viruses. Bacteriophages are extremely specific for certain bacteria, so they do not harm the host body and intestinal microflora, unlike antibiotics. Bacteriophages, also known as phages, infect and can kill bacteria and affect bacterial growth primarily during lytic cycles. Phages insert their DNA into the bacterium, where it is transcribed and used to create new phages, after which the cell will be lysed, releasing a new phage that can infect and destroy other bacteria of the same strain. High phage specificity protects “good” bacteria from destruction.
However, there are some drawbacks to the use of bacteriophages. Bacteriophages may contain virulence factors or toxic genes in their genomes. In addition, oral and intravenous administration of phages to kill bacterial infections poses a much higher safety risk than topical administration, and there is an additional problem of the uncertain immune response to these large antigenic cocktails. There are significant regulatory barriers that must be overcome for such risky treatments. The use of bacteriophages as a substitute for antimicrobials remains an attractive option, despite numerous problems.
The role of plants
Plants are an important source of antimicrobial compounds, and traditional healers have long been using them to prevent or treat infectious diseases. Recently, a new interest has appeared in the use of natural products to identify new antibiotics (defined as natural products with antibiotic activity) and their use in the discovery of antibacterial drugs in the era of genomics. Phytochemicals are an active biological component of plants, and some phytochemicals, including tannins, alkaloids, terpenoids and flavonoids, have antimicrobial activity. Some antioxidant nutritional supplements also contain phytochemicals (polyphenols), such as grape seed extract, and exhibit antibacterial properties in vitro.
Phytochemicals are able to inhibit the synthesis of peptidoglycan, damage the structure of microbial membranes, change the hydrophobicity of the surface of bacterial membranes, and also modulate the sensitivity of the quorum. With an increase in antibiotic resistance in recent years, the potential of new antimicrobial preparations obtained from plants has been studied. Nevertheless, we can say that the long period of discovery of antibiotics has come to an end.