Penicillin Drug Review

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). 

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).

            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. 

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. 

Van Lanen S. 2018 Feb 16. Penicillin Medicinal Chemistry Video. University of Kentucky College of Pharmacy. Lexington (KY). [cited 2018 Sep 23].