Skip to main content

Advertisement

SpringerLink
Log in

Penicillin: the medicine with the greatest impact on therapeutic outcomes

  • Mini-Review
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

The principal point of this paper is that the discovery of penicillin and the development of the supporting technologies in microbiology and chemical engineering leading to its commercial scale production represent it as the medicine with the greatest impact on therapeutic outcomes. Our nomination of penicillin for the top therapeutic molecule rests on two lines of evidence concerning the impact of this event: (1) the magnitude of the therapeutic outcomes resulting from the clinical application of penicillin and the subsequent widespread use of antibiotics and (2) the technologies developed for production of penicillin, including both microbial strain selection and improvement plus chemical engineering methods responsible for successful submerged fermentation production. These became the basis for production of all subsequent antibiotics in use today. These same technologies became the model for the development and production of new types of bioproducts (i.e., anticancer agents, monoclonal antibodies, and industrial enzymes). The clinical impact of penicillin was large and immediate. By ushering in the widespread clinical use of antibiotics, penicillin was responsible for enabling the control of many infectious diseases that had previously burdened mankind, with subsequent impact on global population demographics. Moreover, the large cumulative public effect of the many new antibiotics and new bioproducts that were developed and commercialized on the basis of the science and technology after penicillin demonstrates that penicillin had the greatest therapeutic impact event of all times.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Abraham EP, Newton GGF (1961) The structure of cephalosporin C. Biochem J 79:377–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abraham EP, Newton GGF, Hale CW (1954) Isolation and some properties of cephalosporin N, a new penicillin. Biochem J 58:94–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abraham EP, Newton GGF, Schenck JR, Hargie MP, Olson BH, Schuurmans DM, Fisher MW, Fusari SA (1955) Identity of cephalosporin N and synnematin B. Nature 176:551

    Article  CAS  PubMed  Google Scholar 

  • Arnstein HRV, Morris D (1960) The structure of a peptide containing α-aminoadipic acid, cysteine and valine, present in the mycelium of Penicillium chrysogenum. Biochem J 76:357–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aryanchira S (2010) Overcoming antibiotic-resistant bacteria. Gen Eng Biotechnol News 30(15):18

    Google Scholar 

  • Banko G, Demain AL, Wolfe S (1987) α-(L-α-Aminoadipyl)-L-cysteinyl-D-valine synthetase (ACV synthetase): a multifunctional enzyme with broad substrate specificity for the synthesis of penicillin and cephalosporin precursors. J Amer Chem Soc 109:2858–2860

    Article  CAS  Google Scholar 

  • Batchelor FR, Doyle FP, Nayler JHC, Rolinson GN (1959) Synthesis of penicillin: 6-amino-penicillanic acid in penicillin fermentations. Nature 183:257–258

    Article  CAS  PubMed  Google Scholar 

  • Bost PE, Demain AL (1977) Studies on the cell-free biosynthesis of β-lactam antibiotics. Biochem J 162:681–687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brotzu G (1948) Richerche su di un nova antibiotic. Lavori delll'Instituto d'Igienee di Cagliari 1–11

  • Burton HS, Abraham EP (1951) Isolation of antibiotics from a species of Cephalosporium. Cephalosporins P1, P2, P3, P4 and P5. Biochem J 50:168–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crawford K, Heatley NG, Boyd PF, Hale CW, Kelly BK, Miller GA, Smith N (1952) Antibiotic production by a species of Cephalosporium. J Gen Microbiol 6:47–59

    Article  CAS  PubMed  Google Scholar 

  • Davey YF, Johnson MJ (1953) Penicillin production in corn steep media with continuous carbohydrate addition. Appl Microbiol 1:208–211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Demain AL (1957) Inhibition of penicillin formation by lysine. Arch Biochem Biophys 67:244–246

    Article  CAS  PubMed  Google Scholar 

  • Demain AL (1963) L-Valine: a precursor of cephalosporin C. Biochem Biophys Res Commun 10:45–48

    Article  CAS  PubMed  Google Scholar 

  • Demain AL, Masurekar PS (1974) Lysine inhibition of in vivo homocitrate synthesis in Penicillum chysogenum. J Gen Microbiol 82:143–151

    Article  CAS  PubMed  Google Scholar 

  • Dixon B (2006) Sulfa's true significance. Microbe 1:500–501

    Google Scholar 

  • Fawcett PA, Usher JJ, Abraham EP (1976) Aspects of cephalosporin and penicillin biosynthesis. In: MacDonald KD (ed) Second international symposiumon on the genetics of industrial microorganisms. Academic Press, New York. pp 129–138

  • Fleming A (1929) On the antibacterial action of a Penicillium, with special reference to their use in the isolation of B. influenza. Brit J Exp Pathol 10:226–236

    CAS  Google Scholar 

  • Florey HW, Chain EB, Heatley NG, Jennings MA, Sanders AG, Abraham EP, Florey ME (1949) Antibiotics, vol 2. Oxford University Press, London

  • Friedrich CG, Demain AL (1977) Effects of lysine analogs on Penicillium chrysogenum. Appl Environ Microbiol 34:706–709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gottshall RY, Roberts JM, Portwood LM, Jennings JC (1951) Synnematin, an antibiotic produced by Tilachlidium. Proc Soc Exp Biol Med 76:307–311

    Article  CAS  PubMed  Google Scholar 

  • Hollander IJ, ShenY-Q HJ, Demain AL, Wolfe S (1984) A pure enzyme catalyzing penicillin biosynthesis. Science 224:610–612

    Article  CAS  PubMed  Google Scholar 

  • Jarvis FG, Johnson MJ (1947) The role of the constituents of synthetic media for penicillin production. J Amer Chem Soc 69:3010–3018

    Article  CAS  Google Scholar 

  • Johnson MJ (1952) Recent advances in the penicillin fermentation. Bull World Hlth Org 6:99–121

    CAS  Google Scholar 

  • Kahan FS, Kahan FM, Goegelman RT, Currie SA, Jackson M, Stapley EO, Miller TW, Miller AK, Hendlin D, Mochales S, Hernandez S, Woodruff HB, Birnbaum J (1979) Thienamycin, a new β-lactam antibiotic. I. Discovery, taxonomy, isolation, and physical properties. J Antibiot 32:1–12

    Article  CAS  Google Scholar 

  • Kato K (1953) Occurrence of penicillin-nucleus in culture broths. J Antibiot Ser A 6:184–185

    CAS  Google Scholar 

  • Kohsaka M, Demain AL (1976) Conversion of penicillin N to cephalosporin(s) by cell-free extracts of Cephalosporium acremonium. Biochem Biophys Res Commun 70:465–473

    Article  CAS  PubMed  Google Scholar 

  • Lechevalier H, Acker RF, Corke CT, Haenseler CM, Waksman SA (1953) Candicidin, a new antifungal antibiotic. Mycologia 45:155–171

    Article  Google Scholar 

  • Miller GA, Kelly BK, Newton GGF (1956) Cephalosporin production. British patent 759,624

  • Miller IM, Stapley EO, Chaiet L (1962) Production of synnematin B by a member of the genus Streptomyces. Bacteriol Proc 49:32

    Google Scholar 

  • Moyer AJ, Coghill RD (1946) Penicillin. IX. The laboratory scale production of penicillin in submerged cultures by Penicillium notatum Westling (NRRL 832). J Bacteriol 51:79–93

    Article  PubMed  PubMed Central  Google Scholar 

  • Nagarajan R, Boeck LD, Gorman M, Hamill RL, Higgens CH, Hoehn MM, Stark WM, Whitney JG (1971) β-Lactam antibiotics from Streptomyces. J Amer Chem Soc 93:2308–2310

    Article  CAS  Google Scholar 

  • Olano C, Lombo F, Mendez C, Salas JA (2008) Improving production of bioactive secondary metabolites in actinomycetes by metabolic engineering. Metab Eng 10:281–292

    Article  CAS  PubMed  Google Scholar 

  • Raper KB (1994) The development of improved penicillin-producing molds. Ann NY Acad Sci 48:41–56

    Article  Google Scholar 

  • Reed JC (2011) NCATS could mitigate pharma valley of death. National Center for Advancing Translational Sciences essential to capitalize on basic research. Gen Eng Biotechnol News 31(10):6–8

    Article  Google Scholar 

  • Roberts JM (1952) Antibiotic substances produced by species of Cephalosporium with a description of new species. Mycologia 44:292–306

    Article  Google Scholar 

  • Schatz A, Bugie E, Waksman SA (1944) Streptomycin, a substance exhibiting antibiotic activity against gram-positive and gram-negative bacteria. Proc Soc Exptl Biol Med 55:66–69

    Article  CAS  Google Scholar 

  • Somerson NL, Demain AL, Nunheimer TD (1961) Reversal of lysine inhibition of penicillin production by α-aminoadipioc acid or adipic acid. Arch Biochem Biophys 93:238–241

    Article  CAS  Google Scholar 

  • Spizek J, Novotna J, Rezanka T, Demain AL (2010) Do we need new antibiotics? The search for new targets and new compounds. J Ind Microbiol Biotechnol 37:1241–1248

    Article  CAS  PubMed  Google Scholar 

  • Stapley EO, Jackson M, Hernandez S, Zimmerman SB, Currie SA, Mochales S, Mata JM, Woodruff HB, Hendlin D (1972) Cephamycins, a new family of β-lactam antibiotics. I. Production by actinomycetes, including Streptomyces lactamdurans sp. n. Antimicrob Agents Chemother 2:122–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trown PW, Abraham EP, Newton GGG, Hale CW, Miller GA (1962) Incorporation of acetate into cephalosporin C. Biochem J 84:157–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trown PW, Sharp M, Abraham EP (1963) α-Oxoglutarate as a precursor of the D-α-aminoadipic residue in cephalosporin C. Biochem J 86:280–284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waksman SA, Lechevalier HA (1949) Neomycin, a new antibiotic against streptomycin-resistant bacteria, including tuberculosis organisms. Science 109:305–307

    Article  CAS  PubMed  Google Scholar 

  • Waksman SA, Woodruff HB (1940) Bacteriostatic and bactericidal substances produced by a soil actinomyces. Proc Soc Exptl Biol Med 45:609–614

    Article  CAS  Google Scholar 

  • Weissmann G (2011) Is drug development too slow? NIH to the rescue! FASEB J 25:1110–1122

    Google Scholar 

  • Yoshida M, Konomi T, Kohsaka M, Baldwin JE, Herchen S, Singh P, Hunt NA, Demain AL (1978) Cell-free ring expansion of penicillin N to deacetoxycephalosporin C by Cephalosporium acremonium CW-19 and its mutants. Proc Natl Acad Sci USA 75:6253–6257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

A considerable portion of this review derives from statements made directly by Professor Ernst Chain to one of the authors (NK), who was a graduate student under Professor Chain at Imperial College, London, in 1973–1974.

Author information

Authors and Affiliations

  1. 138 Beacon St., Coatesville, PA, 19320, USA

    Nelson Kardos

  2. Charles A. Dana Research Institute for Scientists Emeriti (R.I.S.E.), Drew University, Madison, NJ, 07940, USA

    Arnold L. Demain

Authors
  1. Nelson Kardos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arnold L. Demain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arnold L. Demain.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kardos, N., Demain, A.L. Penicillin: the medicine with the greatest impact on therapeutic outcomes. Appl Microbiol Biotechnol 92, 677–687 (2011). https://doi.org/10.1007/s00253-011-3587-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-011-3587-6

Keywords

Search

Navigation