Penicillin: The First Antibiotic and the Birth of Modern Medicine

6 min readOct 28, 2021

Today, antibiotics are ubiquitous and accessible to most people in the developed world and are essential in the fields of medicine, agriculture, and biopharmaceutical research [1]. Whether you know it or not, antimicrobials and antibiotics are part of our everyday lives. In general, antibiotics are usually small biomolecules that either kill or halt the growth of bacteria, and can either be naturally occurring or made synthetically [2]. It is easy to overlook the importance of these medicines and take for granted the vast improvement in quality of life they have provided us. In this blog, we hope to illuminate the importance of antibiotics and how they ushered in a new era of human innovation in science and medicine.

The Before Times

Before the use of antibiotics to fight bacterial infections, various chemical solutions and compounds were used to treat illnesses. A German physician named Paul Erlich began his search for a medicinal “magic bullet” that would be able to attack disease without harming the host after observing that some bacteria stained differently [3]. The fact that some bacteria were able to take up dye but not others led him to believe that substances could be created that selectively killed certain bacteria. Erlich eventually would develop what is widely considered the first antibacterial treatment for Syphilis, Salvarsan [4]. Unfortunately, this was far from his imagined “magic bullet” as the drug was arsenic based and killed both bacterial and human cells. Despite this, Salvarsan quickly became the most prescribed drug in the world and is now considered a chemotherapeutic drug by many rather than just an antibiotic.

Another notable figure is British surgeon Joseph Lister. Lister pioneered the movement for aseptic methods during treatment and implemented carbolic acid cleanings in wound care [5]. However, similar to Erlich’s Syphilis treatment, carbolic acid killed both bacterial and human cells. The search for medicine’s “magic bullet” continued after the development of Salvarsan and aseptic methods.

Discovery

The highly romanticized discovery of penicillin by Alexander Fleming is often told as an accidental discovery where a moldy petri dish left near an open window created bactericidal compounds made from the fungi. It is true that Fleming, while tidying his cluttered laboratory, examined that some of his Staphylococcus aureus (bacterium) colonies had been contaminated with the mold Penicillium notatum. He observed that the mold seemed to prevent the normal growth of the staphylococci. The actual isolation of the compound that came to be known as penicillin was a longer, more complicated process that included many other scientists. In truth, Fleming had neither the resources nor background to isolate the active ingredient in the “mold juice” that killed bacteria [6].

For this task, he was aided by Dr. Howard Florey and Dr. Ernst Chain. Chain and Florey were able to successfully scale up penicillin production and prove that the compound could kill bacteria in mice [7]. Shortly after, it was shown to kill bacteria in humans. After much research and development, penicillin was able to be produced in mass quantities and increased availability on an industrial scale. The drug proved its might during WWII, where it was able to decrease the death rate of bacterial pneumonia from 18% in WWI to just below 1% [8]. This marked a watershed moment in human history as life expectancy rose dramatically after the discovery of penicillin. Childbirth, surgery, and small cuts were no longer a death sentence.

The discovery of penicillin ushered in a race to find the next antibiotics. The period from 1950–1960 is often referred to as the golden age of antibiotic discovery, as the majority of commonly used antibiotic drugs used today were discovered during this period [9]. However, the ubiquity of antibiotics has posed a new problem in modern medicine.

A New Era

The overuse of antibiotics has resulted in increasing resistance among dangerous disease-causing bacteria, with penicillin-resistant bacteria being discovered as early as 1947 [10]. One of the World Health Organization’s main priorities is developing treatments and policies for multidrug resistance tuberculosis (MDR-TB), which poses a threat globally as a growing percentage of TB infections are extensively drug-resistant (XDR-TB) [11]. Antibacterial resistance has pushed drug discovery to find more potent compounds to kill bacteria, though this often comes with increasing side effects. More potent drugs that may kill the disease causing bacteria can harm the patients by damaging our own microbiomes and in some instances, our own cells.

Recent data has shown that we do not live our lives alone; we have commensurate and beneficial relationships with non-pathogenic bacteria that live on and in us [12]. The vast majority of bacteria are non-pathogenic and although antibiotics serve as magic bullets for humans, they indiscriminately kill most bacteria. By upsetting our microbiomes, this can also induce some usually non-pathogenic bacteria to become pathogenic opportunistically with decreased bacterial competition [13]. Other side effects of an upset microbiome are indigestion and decreased immune responses.

How does Penicillin Actually Work?

Core structure of penicillin. Provided by user isizawa from Pixabay

To understand how bacterial resistance can develop, it is useful to understand how antibiotics work. Penicillin in particular is a beta-lactam antibiotic. Beta-lactams are a class of antibiotics that target the cell walls of bacteria. Bacterial cell walls are made of peptidoglycan which form polymers by crosslinking to each other and forming a sort of mesh. Beta-lactams target the enzyme that catalyzes this crosslinking reaction to prevent the formation of bacterial cell walls [14].

Bacteria with a peptidoglycan (mesh of sugars and amino acids) outer cell wall are referred to as gram-positive, because they give a positive result in a Gram stain test. Because beta-lactams target peptidoglycan formation, they’re least effective on gram-negative bacteria. This is due to the extra membrane they have shielding their (inner) peptidoglycan membrane. Gram-negative bacteria likely don’t have as many antibiotic-resistant genes since they haven’t needed them as much as their counterparts. Finally, to aid in preventing further antibiotic resistance, the ideal approach would be development of antibiotics that target only a few bacteria (like penicillin). This type of antibiotics are considered narrow spectrum antibiotics [16] (their opposite being broad spectrum antibiotics). Generally, the use of the most narrow spectrum drugs for a particular infection can help prevent the development of drug resistance bacteria.

Takeaways

When developing new antibiotics, the first step is to identify the differences in bacterial and human morphology. Any differences can be taken advantage of to be used as targets to selectively kill bacteria without harming humans. The four major targets are cell wall synthesis, DNA replication, protein synthesis, and bacterial metabolism. As antibiotic resistance continues to grow, the race to discover new drugs becomes more difficult as the targets have had time to become more and more obscure.

Penicillin changed how we think about disease and ushered in a new era of pharmaceutical research on real life “magic bullets”. The discovery of penicillin and antibiotics has saved countless lives, controlled the spread of infectious diseases, and eliminated the leading causes of morbidity and mortality for most of human history. Although the antibiotic era has greatly increased the quality of life in the modern era, it did not come without a cost. Antibiotic resistance is a growing problem that disproportionately affects populations of lower socioeconomic status. Our microbiomes are also susceptible to being damaged by the constant overuse of antibiotics in both our medicines and agriculture. The evolutionary battle between bacteria and humans have led to medical innovation and continues to be at the forefront of biopharmaceutical research. Improving antibiotics by fighting resistance through reduced use, complementary treatment, and funding research can ensure that we will have antibiotics as tools in medicine, agriculture, and pharmaceutical research well into the future.