“Do you have a viral infection? Then you should take antibiotics!” has always been an anathema to microbiologists. However, this thread of logic is surprisingly commonplace. Before delving into the history of antibiotics it is important to set the record straight. Antibiotics are used to treat bacterial infections and are completely ineffective against viruses, which are inhibited by antiviral drugs.
The discovery of antibiotics is inspired from nature where microbes are always battling each other in order to dominate a particular habitat. Sometimes this entails secreting toxic molecules that can destroy other microbes, reducing the ability of certain host microbes to dominate. Some of the earliest antibiotics were discovered when scientists chanced upon these toxic molecules and then used them to combat bacterial infections.
The earliest records of treating microbial infections date back to ancient Egypt in 1500 BC. They discovered by trial and error, that the bread that had been infected by fungus could be used to cure bacterial infections. As disgusting as this may sound, this treatment was commonplace all over the world. The Greeks in 16th century BC would use fungus scraped from cheese to treat wounded soldiers, whereas the Chinese used moldy soya beans, and aborigines in Australia used mold that grew in the shade of eucalyptus trees.
A more palatable source of antibiotics was discovered in the 1990s during the investigation of Nubian mummies. These mummies, dated back to 350-550 AD, contained the antibiotic tetracycline in their bones. This antibiotic, named because of its four-ringed structure was produced from contaminating Streptomyces bacteria which grew in beer. The bacteria were competing against the yeast that was also present in the beer, thus leading to the production of antibiotics.
The systematic search for antibiotics began with the observation that bacteria could be stained with certain dyes. Therefore, it could be argued that if dyes could enter bacterial cells, chemicals could do the same. In 1900, Paul Ehrlich, a German physician hypothesized the concept of a magic bullet, a compound that could be used to only kill bacteria without damaging the human body. After several trials, he was successful in finding the first magic bullet in 1909; the compound Salvarsan, meaning “saving arsenic”, was very effective in curing syphilis, which is caused by the bacteria Treponema pallidum.
Although this drug became an instant success around the world, it was controversial. because of the serious side effects such as nausea and vomiting. Ehrlich was accused of criminal negligence in what came to be known as the Salvarsan Wars.
Another famous synthesized antibiotic, Prontosil, was developed in 1932. This antibiotic was the first sulfa drug. Unlike Salvarsan, Prontosil and other sulfa drugs were effective against a wide range of infectious bacteria, which was why they remained popular well into World War II. In fact, the dependence of the German troops on these drugs ultimately tipped the balance of the war in favor of the Allied troops.
The antagonism between mold and bacteria was observed by several scientists in the 19th century who recognized specific strains of fungi, such as Penicillium – used to produce cheese, would also be resistant to bacterial contamination. The specific molecule, penicillin, that was responsible for this inhibition was recognized in 1928 by Alexander Fleming, a Scottish physician. The serendipitous discovery of penicillin is best described by the quote “Chance favors the prepared mind” by Louis Pasteur, another giant in the field of microbiology.
Fleming was on the search of a compound that could inhibit the growth of bacteria. He was studying the properties of Staphylococci, a group of bacteria that frequently colonized the skin and upper respiratory tract of animals resulting in infections. Fleming’s lab was frequently untidy, and as a result, some of the bacterial cultures were contaminated by a fungus. He noticed that the bacterial colonies, close to the fungus were killed, but those further away remained normal. Upon seeing this he famously remarked “That’s funny“, an expression that has probably been used by countless scientists over the years whenever they have made interesting discoveries. Fleming identified the fungus as being a Penicillium species, and after some months of calling the inhibitor by an eloquent name of “mould juice”, he renamed it as penicillin.
Unfortunately, Fleming could not characterize penicillin further because he lacked the knowledge and skill required to do so. He was helped by Howard Florey, an Australian pharmacologist, and Ernst Chain, a British biochemist. Florey and Chain studied the therapeutic action of penicillin and discovered how to concentrate the active ingredient in penicillin that was responsible for its killing action. Subsequently, all three of them received the Nobel Prize for Physiology or Medicine in 1945 for their work on penicillin.
Later Florey’s research team attempted to mass-produce penicillin, a herculean task because massive volumes of the fungal cultures were needed to be grown to get a reasonable yield of the drug. Inspired by Florey’s work, several companies in the U.S. and United Kingdom began working on producing penicillin with an objective of having enough supply for the D-day invasion of Europe. Finally, the mass production of penicillin was successfully standardized by the Northern Regional Research Laboratory (NRRL) in Peoria, Illinois.
As a result, the United States had an unlimited supply by 1944, which was one of the reasons why the Allied troops had an advantage over the Germans, who were content with the use of sulfa drugs and did not invest much effort in the production of penicillin. The “wonder drug” was far superior to any of the drugs available at that time and thousands of Axis troops died from wound infections and venereal diseases that could have been easily cured by penicillin. Interestingly penicillin saved the life of Hitler after a botched assassination attempt left him wounded. His physician at the time was aware of the effects of penicillin and could, therefore, treat Hitler.
Following the discovery of penicillin, several new classes of antibiotics were discovered between the 1950s and 1970s. These antibiotics are categorized based on their chemical structure, the bacteria they target, and their mechanism of action. Unfortunately, the era of antibiotic discovery went into a hiatus for almost 40 years, and new classes of antibiotics were discovered only in the late 2000s and early 2010s. The primary reason for this reduced pace is that previously antibiotics were discovered by testing the inhibitory activity of various chemical compounds. Therefore, the low hanging fruits were already known, and it became harder to find new and effective chemicals. Additionally, even the latest antibiotics that were discovered in the 2000s belonged to antibiotic classes that had already been described between 1950 and 1970. This underscores the main problem with antibiotic discovery – limited chemical diversity among antibiotics, and that they must enter the bacteria and should not be pumped out, which excludes a wide array of chemicals.
A second, and more terrifying, the problem is the ability of bacteria to gain resistance to antibiotics. Bacteria have the remarkable capability of mutating the pathways targeted by antibiotics and thus gain resistance. To further complicate this, bacteria can pass on this information to other bacteria via horizontal gene transfer leading to a further increase in antibiotic resistance in the bacterial population. These antibiotic-resistant strains also called “superbugs“, have become progressively harder to treat. Antibiotic resistance now is considered a global threat. According to the CDC, superbugs cause 23,000 deaths per year in the U.S. alone.
So how can we combat the growing incidences of drug-resistant bacteria? “The first rule of antibiotics is try not to use them, and the second rule is try not to use too many of them” is an excellent lesson mentioned in The ICU Book. This adage is an important step in reducing the instances of antibiotic resistance. Self-prescription, incorrect prescription, such as using antibiotics to combat viral infections, and overuse of antibiotics all contribute to an increase in resistant bacterial strains.
Several measures have been taken by the scientific community to address the problems created by antibiotic use and combat the emergence of drug-resistant bacteria. These measures include changing the targets of antibiotics and using novel chemicals or other agents to target bacteria.
Historically, antibiotic synthesis has followed a pattern: an accidental discovery followed by an investigation of the inhibitory/killing action in order to pinpoint bacterial targets, which includes the cell wall, the machinery involved in DNA and protein synthesis, to name a few. However, it is now possible to identify several novel targets in bacteria and design the antibiotic accordingly. The caveat is that these targets need to be essential to the bacteria so that they are not mutated easily. Alternatively, there have been attempts at developing antibiotics that target various cellular processes simultaneously. This could reduce the probability of bacteria developing resistance, as the likelihood of it mutating multiple pathways at the same time is very low.
There have also been attempts at using chemicals from plants as a potential source of antibiotics. Plants produce several compounds that have demonstrated antibacterial activity. Another bacterial enemy that can be used are phages – viruses that have evolved to target bacteria. Unlike some antibiotics that indiscriminately kill bacteria, phages can be used to selectively kill the pathogenic strains leaving the useful bacteria unaffected. Thus, the ‘war between science and bacterial invaders’ rages on.
Author:
Ananya Sen is currently a Ph.D. student in Microbiology at the University of Illinois at Urbana-Champaign. When she’s not studying oxidative stress, she is busy pursuing her passion for scientific writing. Currently, she contributes articles to ASM, ScienceSeeker, and her own blog where she discusses the history of various scientific processes. She is an ardent reader and will happily discuss anything from Jane Austen to Gillian Flynn. Her graduation goals include covering all the national parks in the U.S. with her sidekick Oscar, a Schnauzer/Pomeranian mix.
Illustrator:
Arghya Manna is a comics artist, illustrator, and a Ph.D. dropout. He began his career as a doctoral student at Bose Institute, India. He had been working on Tumor Cell migration in a 3D environment. Along with this, he was an active participant in several projects related to tumor immunology and cancer stem cell. After leaving the lab without bagging the degree Arghya found refuge in art and got involved in drawing comics. He is an enthusiast in History of Science and has been running a blog named “Drawing History of Science”. Arghya wishes to engage the readers of history and science with the amalgamation of images and texts.
Editors:
Roopsha Sengupta is the Editor-in-Chief at ClubSciWri. She did her Ph.D. at the Institute of Molecular Pathology, Vienna and postdoctoral research at the Gurdon Institute, University of Cambridge, UK, specializing in the field of Epigenetics. During her research, she was involved in many exciting discoveries and had the privilege of working and collaborating with a number of inspiring scientists. As an editor for ClubSciWri, she loves working on a wide range of topics and presenting articles coherently, while nudging authors to give their best.
Paurvi Shinde 
is a Post Doc Fellow at Fred Hutchinson Cancer Research Center, where she studies how some receptors expressed on regulatory T cells can alter their phenotype and function during HSV-2 infection. Apart from science, she loves writing/editing scientific articles to make them easy and fun to read and enjoys other roles such as career guidance of students (school/high school) studying at Freedom English Academy (New Delhi, India) and participating in career building events organized by Women in Bio organization. Follow her on Linkedin.
Blog design: Paurvi Shinde
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