By Hannah Johnson

Some of the first antibiotics found to treat bacterial infections were discovered in the late 1800s and early 1900s by Paul Ehrlich and Alexander Fleming, starting the antibiotic era. Ehrlich is credited for the idea of a chemical compound capable of selectively targeting microbes while leaving the host cells alone. Ehrlich is also known for establishing the process of large-scale drug screening, which is still being used for drug discovery even now⁶. With his ideas, Ehrlich discovered the drug salvarsan and its ability to treat syphilis in 1909⁶. Until 1942, salvarsan was the most prescribed drug, then penicillin entered the scene⁶.

Many people might find the story behind penicillin’s accidental discovery familiar. On September 3^rd, 1928, Fleming, a bacteriologist, came back from a summer vacation to his work at St. Mary’s Hospital in London and observed a curious finding^2,3,6. When looking at petri dishes containing colonies of the bacteria, Staphylococcus aureus, under a microscope, Fleming found that one of the petri dishes contained mold, later identified to be a strain of Penicillium notatum³. He observed that the area surrounding the mold was clear of any bacteria, indicating a secretion by the mold was inhibiting the bacterial growth. Fleming published these findings in the British Journal of Experimental Pathology with a brief mention of possible therapeutic applications, unaware of what his work would eventually lead to^2,3.

The initial obstacle in exploring the therapeutic uses of penicillin was in the immense difficulties in extracting the secretion successfully. For instance, the compound was unstable, and early researchers struggled to identify and isolate the active material^5,9. This work was eventually taken up by Howard Florey and Ernst Chain from Oxford University, where, through their work in its extraction and purification, they were able to transform penicillin into the drug it is today^3,6. Florey and Chain were able to optimize the purification process enough for the drug to undergo animal trials, where it was observed to protect mice from infection with Streptococcus pyogenes, Staphylococcus aureus, and Clostridium septique⁸. Eventually this led to the first use in humans, where, in 1941, Albert Alexander cut his mouth while tending to his garden causing a life-threatening infection^2,3,6. Once penicillin was injected, he showed remarkable recovery within days; however, with limited supply at the time, the drug unfortunately ran out before Alexander could make a complete recovery and he succumbed to his infection. Since penicillin had been found to counter a large variety of bacterial infections and there was an increasing need of a such a drug in World War II, Florey and Chain brought their efforts to the pharmaceutical industries. This allowed for further optimization of penicillin processing to meet the high demand. Eventually, the first successful treatment with penicillin was achieved in Anne Miller in 1942, and within a few months, ten more cases were also treated successfully^2,3,6. The drop-in death rates of bacterial pneumonia from 18% in World War I to 1% in World War II showed penicillin’s great capacity for treating bacterial infections².

To this day, penicillin is one of the most used antibiotics in the world. This is in large part due to its range of effectiveness in treating bacterial infections with gram-positive and gram-negative bacteria, which are different types of bacteria classified by their cell wall⁴. However, there have been indications of bacterial resistance to penicillin, as in the case of enterococci, which requires the combination therapy of penicillin with streptomycin or gentamicin⁴. Although penicillin has been shown to be ineffective against gram-negative rod bacteria, the second-generation penicillins, amoxicillin and ampicillin, are able to inhibit these bacteria where the first-generation cannot⁴. In total, there have been four generations of penicillins developed to further the applications of these antibiotics. Penicillin works to inhibit bacteria by preventing the cross-linking of peptidoglycan in the bacterial cell wall. This weakens the bacterial cell wall to the point where osmotic pressure allows water to enter and kill the cell⁴. The effects of penicillin can be enhanced when used in combination with a beta-lactamase inhibitor, which is an enzyme some bacteria produce to degrade beta-lactams such as pencillin⁴. This combination allows some resistant bacteria to be overcome by inhibiting their capacity for degrading penicillin.

Although the contributions of penicillin to the field of antimicrobials is vast, the development of antimicrobial resistance is becoming an increasingly relevant concern. A report commissioned by the UK found that with the increase in antimicrobial resistance, it is projected that 10 million people will die every year by 2050 due to this resistance⁷. This rising bacterial resistance towards the current antibiotics has contributed the push needed in growing the development of new antibiotics to address this concern. This is seen in the drug, murepavedin, which has been shown to be effective against drug-resistant P. aeruginosa and is currently in Phase III clinical trials^5. In total, 45 new antibiotics were in US clinical trials as of December 2018, showing that this resistance is being overcome with the production of new antibiotics⁵.

TL: DR

The discovery of penicillin led to one of the most used antibiotics in the world. Though bacterial resistance to antibiotics continues to grow, new antibiotics are being developed to overcome this challenge.

---

References

1. https://www.istockphoto.com/photos/penicillin-pills
2. https://www.pbs.org/newshour/health/the-real-story-behind-the-worlds-first-antibiotic
3. https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html
4. Yip, Derek W., and Valerie Gerriets. “Penicillin.” (2020).
5. Hutchings, Matthew I., Andrew W. Truman, and Barrie Wilkinson. “Antibiotics: past, present and future.” Current opinion in microbiology 51 (2019): 72-80.
6. Aminov, Rustam I. “A brief history of the antibiotic era: lessons learned and challenges for the future.” Frontiers in microbiology 1 (2010): 134.
7. Neil, J. O. “Report on Antimicrobial Resistance.” (2016).
8. Chain, Ernst, et al. “Penicillin as a chemotherapeutic agent.” The lancet 236.6104 (1940): 226-228.
9. Gaynes, Robert. “The Discovery of Penicillin—New Insights After More Than 75 Years of Clinical Use.” Emerging Infectious Diseases vol. 23,5 (2017): 849–853. doi:10.3201/eid2305.161556