In this discovery mini-review, the assigned drug of interest is Penicillin. There are many aspects of this drug and its discovery that are worth more than a one-page paper, but I will concisely summarize the key points for this medication’s history here. The story of the discovery of Penicillin is very interesting and begins in Dr. Alexander Fleming’s Laboratory in 1928. He had been culturing agar plates with Staphylococcus species when he realized that one plate had a mold growing on it that appeared to inhibit the growth of the surrounding bacteria. Upon further review and after a published paper, the scientific and pharmaceutical communities began a deep search for how to manufacture and produce this medication on a large scale, and during 1944, Pfizer officially opened the first commercial plant dedicated to Penicillin production for WWII (ACS 2015).
Penicillin is a naturally occurring compound produced by the mold Penicillium rubens(formerly Penicillium chrysogenum) and was the first commercially available antibiotic. The Penicillin form that is gathered from the mold itself is the form known as Penicillin G. The form we are familiar with in retail pharmacy is Penicillin V, and is formed from the Penicillin G molecule, but is a semi-synthetic medication (Houbraken et al 2011). The semi-synthetic nature of Penicillin V versus Penicillin G stems from the addition of a phenoxyacetyl side chain via a reaction with phenoxyacetyl chloride in triethylamine. The completion of the reaction also requires the use of an N,N’-dicyclohexylcarbodiimide (DCC)-mediated reaction (KCN 2014). The production of Penicillin is performed by allowing Penicilliummolds to grow inside of deep fermentation tanks where the secreted Penicillin-containing broth is collected, separated, and finally purified into a usable form that is safe for humans (NLM 2018).
There are many moving parts and very specific mechanisms that go into the production of Penicillin on a large scale. At first, Pfizer was just operating with large flasks and pans which enabled them to produce Penicillin via fermentation, albeit frustratingly slow. They purchased an old refrigeration plant and transformed this building into the World’s first Penicillin production plant. With this new plant, the idea was to implement deep-tank fermentation so that the quantities of Penicillin obtained would be drastically improved. They began with fourteen 7,500-gallon tanks which enabled them to become the leading producer of Penicillin during war time. The commercialization of Penicillin after WWII would not have been possible without deep-tank fermentation, and thus it is important to briefly delve into how this process works. There is a large tank, generally within the range of 7,500 gallons to 50,000 gallons, which contains a Sparger at the bottom that produces air bubbles using electricity and sterile air. The oxygenated air is spun and transported throughout the tank via motorized impellers. There is an acid-base pump that maintains the pH relatively stable at about 6.5, and an exhaust for the by-products of fermentation to escape. The collection tube is located beneath the tank and the Penicillin broth is harvested from that tube, then purified further (ACS 2015).
Penicillin V targets the Penicillin-binding Protein (PBP) on the cell walls of bacteria to inhibit the final step in the transpeptidation of peptidoglycan. More specifically, the drug molecule irreversibly and covalently acylates the bacterial transpeptidase, PBP, responsible for uniting the terminal glycine residue of one pentapeptide with the D-alanine residue on a neighboring pentapeptide, thus blocking the final step in peptidoglycan biosynthesis and eventually leading to bacterial cell lysis (KCN 2014). This medication has been widely used for decades and the current clinical, labeled indications include Fusospirochetosis (i.e., dental-related pharyngitis), Pneumococcal infections, Rheumatic fever, Staphylococcus infections, and Streptococcus infections (Lexicomp 2018). As with many – if not all – medications, there are adverse reactions associated with its use. Comparatively speaking, these are mild and less numerous than other common antibiotics and the most common reactions include nausea, vomiting, and diarrhea. Some less common, but more severe, reactions include acute interstitial nephritis, anaphylaxis, dermatitis, fever, anemia, and serum-sickness (Lexicomp 2018).
There were some issues with Penicillin G when it was first manufactured: it was only injectable and could not be taken orally, it is prone to antibiotic resistance via beta-lactamases, it had a narrow therapeutic spectrum, and had poor acid stability. Penicillin V was able to tackle the issues regarding acid stability and route of administration, but the resistance factors and narrow spectrum still were issues of interest for pharmaceutical companies (Van Lanen 2018). The initial scientific studies were conducted by the Office of Scientific Research and Development, OSRD, before and during 1943. There were 57 research contracts in total during a 3-year span which included preliminary studies, clinical trials, and research into the medication’s chemical synthesis. An important fact to note here is that the completion and scaling of manufacturing for Penicillin was on a very demanding schedule due to it’s potential as a life-saving drug for the WWII soldiers. This fact is why the government and the War Production Board, WPB, were able to coordinate all of these efforts between themselves and 21 other pharmaceutical operations located within the US (Quinn 2013).
The commercialization of Penicillin has, perhaps, one of the most interesting histories of any medication production process. As mentioned, the process of rapidly commercializing a medication for use during war time takes a collaborative effort from all players to successfully aid the campaign. Penicillin is the greatest example of collaborative war time production, and there were three main variables that allowed this to happen. The first is that Alexander Fleming did not patent the drug molecule itself because he and others thought that placing a patent on a life-saving medication would be unethical. Second, the traditional barriers presented by the patent process were no longer an issue for the manufacturers, and thus, they were free to exchange information and perform reciprocal licensing on all the information regarding the production of Penicillin. The third factor was that the government was the holder of 32 process patents, but due to government policy, they allowed any company to access the information and use it without having to pay royalties (Quinn 2013).
Contemporarily, there are generic drug manufacturers all around the World supplying Penicillin VK at low-cost, and there are too many to list in this paper (see Antimicrobe.org for full list of current or former brand names). Some notable producers include Teva Pharmaceuticals, Eli Lilly, and GlaxoSmithKline just to name a few. There are currently 15 branded medications that incorporate Penicillin V potassium into their product along with 37 New Drug Applications that also include Penicillin V potassium in some way (DrugPatentWatch 2018).
In reflection, the aspect I found most compelling for the drug’s development was the core moiety’s (i.e., the penam core) ability to be altered in a large variety of ways which led to many therapeutic options after the synthesis of Penicillin was fully realized. The side chain region of the penam core was the specific aspect of this drug’s developmental pathway that allowed for the large number of possible chemical modifications to take place, and with them, the multiple options for therapy we now have today.
References
[ACS] American Chemical Society. 2015 Nov 5. ACS Chemical Landmarks: Alexander Fleming, Discoverer of Penicillin. < https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/fleming penicillin.html >. Accessed 2018 Sep 23.
[Antimicrobe.org] 2017. Penicillin Brand Names/Manufacturers Page. < http://www.antimicrobe.org/drugpopup/Penicillin%20-%20Brand%20names.htm >. Accessed 2018 Oct 29.
[DrugPatentWatch] thinkBiotech LLC. 2018. Penicillin V – Generic Drug Details. < https://www.drug
patentwatch.com/p/ingredient/index.php?query=PENICILLIN%20V >. Accessed 2018 Oct 29.
Houbraken J, Frisvad JC, Samson RA. 2011. Fleming’s penicillin strain is not Penicillium chrysogenum but P. rubens. Global Myco J 2(1): 87-95. In: National Center for Biotechnology Information [Internet]. Uppsalalaan (Netherlands): NCBI-PMC; [cited 2018 Sep 23]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317369/#__ffn_sectitle; PMCID: PMC3317369.
[KCN] The KCN Chemistry Group. 2014. KCN Sample PDFs: Penicillin. < http://nicolaou.rice.edu/pdfs/Sample_Chapter13.pdf >. Accessed 2018 Sep 23.
[Lexicomp] Walters Kluwer Clinical Drug Information. 2018 Sep 11. Lexicomp Lexidrug Database: Penicillin V. < https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7461 >. Accessed 2018 Sep 23.
[NLM] U.S. National Library of Medicine. 2018 July 5. NLM Databases: Exhibits and Collections.
< https://vsearch.nlm.nih.gov/vivisimo/cgi-bin/query-meta?v:project=nlm-main-website&binning-state=group%3d%3dExhibits%20%26%20Collections&query=Penicillin >. Accessed 2018 Sep 23.
Quinn R. 2013. Rethinking Antibiotic Research and Development: World War II and the Penicillin Collaborative. Am J Public Health 103(3): 426-434. In: National Center for Biotechnology Information [Internet]. Salt Lake City (UT): NCBI-PMC; [cited 2018 Oct 29]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673487/; PMCID: PMC3673487.
Van Lanen S. 2018 Feb 16. Penicillin Medicinal Chemistry Video. University of Kentucky College of Pharmacy. Lexington (KY). [cited 2018 Sep 23].
