Different roads to discovery; Prontosil (hence sulfa drugs) and penicillin (hence β-lactams)

  • Ronald Bentley


The important chemotherapeutic agents, Prontosil and pentenylpenicillin (penicillin F), were investigated initially by two men, Domagk and Fleming, who had been influenced by the horrendous wound infections of World War I. The very different pathways leading to their development and to that of the successor antibacterials (sulfa drugs, further penicillins, semi-synthetic penicillins), including the role played by patents, are discussed.


Prontosil Penicillins Sulfanilamide Sulfa drugs Semi-synthetic penicillins Submerged fermentation Patents Domagk Fleming Florey Chain 



I thank Philip Eagle of the British Library for information on British and European patents, Ruediger Borstel of Bayer Corporate History and Archives, and Thomas Hager for correspondence concerning Prontosil. Thanks are also due to A. Demain for helpful comments after reading a draft of this paper. A reviewer is thanked for useful suggestions.


  1. 1.
    Abraham EP, Chain E, Fletcher CM, Florey HW, Gardner AD, Heatley NG, Jennings MA (1941) Further observations on penicillin. Lancet 2:177–189 (issue of August 16)Google Scholar
  2. 2.
    Anderson S, Homan P (2002) Best for me, best for you––a history of Beecham’s pills. Pharm J 269:921–924Google Scholar
  3. 3.
    Behr A (1909) Food product and process of making same. US Patent 914,379Google Scholar
  4. 4.
    Behrens OK, Corse J, Jones RG, Mann MJ, Soper QF, Van Abeele FR, Chiang M-C (1948) Biosynthesis of penicillins I. Biological precursors for benzylpenicillin (penicillin G). J Biol Chem 175:751–764PubMedGoogle Scholar
  5. 5.
    Bentley R (1991) Holding a mirror to penicillin—a reflection. Biochemist 13:31Google Scholar
  6. 6.
    Bentley R (2004) The molecular structure of penicillin. J Chem Educ 81:1462–1470CrossRefGoogle Scholar
  7. 7.
    Bentley R, Bennett JW (2003) What is an antibiotic? Revisited. Adv Appl Microbiol 52:303–331. doi: 10.1016/S0065-2164(03)01012-8 PubMedCrossRefGoogle Scholar
  8. 8.
    Bentley R, Bennett JW (2008) A ferment of fermentations. Reflections on the production of commodity chemicals by microorganisms. Adv Appl Microbiol 63:1–32. doi: 10.1016/S0065-2164(07)00001-9 PubMedCrossRefGoogle Scholar
  9. 9.
    Bickel L (1972) Rise up to life. Angus and Robertson, LondonGoogle Scholar
  10. 10.
    Birkinshaw JH (1972) Harold Raistrick 1890–1971. Biogr Mem Fellows R Soc 18:489–509. doi: 10.1098/rsbm.1972.0017 PubMedGoogle Scholar
  11. 11.
    Brown K (2004) Penicillin man. Alexander Fleming and the antibiotic revolution. Sutton Publishing, ThruppGoogle Scholar
  12. 12.
    Bryskier A (2003) Gerhard Johannes Paul Domagk. Chemother J 12:97–105Google Scholar
  13. 13.
    Bud R (1998) Penicillin and the new Elizabethans. Br J Hist Sci 31:305–333. doi: 10.1017/S0007087498003318 CrossRefGoogle Scholar
  14. 14.
    Chain E, Florey HW, Gardner AD, Heatley NG, Jennings MA, Orr-Ewing J, Sanders AG (1940) Penicillin as a chemotherapeutic agent. Lancet 2:226–228 (issue of August 24)Google Scholar
  15. 15.
    Clark RW (1985) The life of Ernst Chain. Penicillin and beyond. Weidenfeld and Nicolson, LondonGoogle Scholar
  16. 16.
    Clarke HT, Johnson JR, Robinson R (1949) The chemistry of penicillin. Princeton University Press, Princeton NJGoogle Scholar
  17. 17.
    Clutterbuck PW, Lovell R, Raistrick H (1932) The formation from glucose by members of the Penicillium chrysogenum series of a pigment, an alkali-soluble protein and penicillin––the antibacterial substance of Fleming. Biochem J 26:1907–1918PubMedGoogle Scholar
  18. 18.
    Colebrook L (1964) Gerhard Domagk 1895–1964. Biogr Mem Fellows R Soc 10:39–50. doi: 10.1098/rsbm.1964.0003 Google Scholar
  19. 19.
    Colebrook L, Kenny M (1936) Treatment of human puerperal infections, and of experimental infections in mice with Prontosil. Lancet 1279–1286 (issue of June 6)Google Scholar
  20. 20.
    Demain AL (2004) Pickles, pectin, and penicillin. Annu Rev Microbiol 58:1–42. doi: 10.1146/annurev.micro.58.030603.123757 PubMedCrossRefGoogle Scholar
  21. 21.
    Demain AL, Martin JF, Elander RP (1998) Penicillin biochemistry and genetics. In: Mateles RI (ed) Penicillin: a paradigm for biotechnology. Candida Corp, Chicago, IL, pp 93–114Google Scholar
  22. 22.
    Domagk G (1935) Ein Beitrag zur Chemotherapie der bakterillen Infektionen. Deutsch Med Wochenschrift 61:250-253 (for English translation see Brock TD Milestones in Microbiology [1961]. American Society for Microbiology, Washington DC)Google Scholar
  23. 23.
    Domagk G (1936) Chemotherapie der streptokokken-infektionen. Klin Woch 15:1585–1590. Retitled as J Mol Med. doi: 10.1007/BF01780820 Google Scholar
  24. 24.
    Domagk D (1957) Twenty-five years of sulfonamide therapy. Ann NY Acad Sci 69:380–384. doi: 10.1111/j.1749-6632.1957.tb49674.x PubMedCrossRefGoogle Scholar
  25. 25.
    Dunnill M (2000) The Plato of Praed street. The life and times of Almroth Wright. Royal Society of Medicine Press Ltd., LondonGoogle Scholar
  26. 26.
    Du Vigneaud V, Carpenter FH, Holley RW, Livermore AH, Rachele JR (1946) Synthetic penicillin. Science 104:431–433. doi: 10.1126/science.104.2706.431 PubMedCrossRefGoogle Scholar
  27. 27.
    Fleming A (1929) On the antibacterial action of cultures of a Penicillium with special reference to their use in the isolation of B. influenzae. Br J Exp Pathol 10:226–236Google Scholar
  28. 28.
    Foster JW, McDaniel LE (1943) Process for the production of penicillin. US Patent 2,448,790Google Scholar
  29. 29.
    Foster JW, McDaniel LE (1946) Production of penicillin in cotton-seed meal medium. US Patent 2,448,791Google Scholar
  30. 30.
    Hager T (2006) The demon under the microscope. Harmony Books, New YorkGoogle Scholar
  31. 31.
    Hare R (1970) The birth of penicillin and the disarming of microbes. George Allen and Unwin Ltd., LondonGoogle Scholar
  32. 32.
    Henry TA (1952) Obituary notice. Ernest Fourneau 1872–1949. J Chem Soc 261–266. doi: 10.1039/jr9520000261
  33. 33.
    Hobby GL (1985) Penicillin. Meeting the challenge. Yale University Press, New HavenGoogle Scholar
  34. 34.
    Kato K (1953) Occurrence of penicillin-nucleus in culture broths. J Antibiot 6:130–136PubMedGoogle Scholar
  35. 35.
    Lesch J (2007) The first miracle drugs. How the sulfa drugs transformed medicine. Oxford University Press, New York, NYGoogle Scholar
  36. 36.
    Macfarlane RG (1979) Howard Florey. The making of a great scientist. Oxford University Press, OxfordGoogle Scholar
  37. 37.
    Mateles RI (ed) (1998) Penicillin: A paradigm for biotechnology. Candida Corp, Chicago, ILGoogle Scholar
  38. 38.
    Maurois A (1959) The life of Sir Alexander Fleming. EP Sutton & Co In, New YorkGoogle Scholar
  39. 39.
    Mietzsch F, Klarer J (1932) Verfahren zur Herstellung von Azoverbindungen. Reichspatent 607:537Google Scholar
  40. 40.
    Moyer AJ (1945) Method for production of penicillin. US Patent 2,442,141Google Scholar
  41. 41.
    Moyer AJ (1945) Method for production of penicillin. US Patent 2,443,989Google Scholar
  42. 42.
    Moyer AJ (1945) Method for production of penicillin. US Patent 2,476,107Google Scholar
  43. 43.
    Moyer AJ (1945) Improvements in or relating to methods for producing penicillin. British Patent 618,415Google Scholar
  44. 44.
    Moyer AJ (1945) Improvements in or relating to methods for producing penicillin. British Patent 618,416Google Scholar
  45. 45.
    Moyer AJ (1945) Improvements in or relating to methods for producing penicillin. British Patent 624,411Google Scholar
  46. 46.
    Moyer AJ, Coghill RD (1946) Penicillin VIII. Production of penicillin in surface cultures. J Bacteriol 51:57–78PubMedGoogle Scholar
  47. 47.
    Moyer AJ, Coghill RD (1947) Penicillin X. The effect of phenylacetic acid on penicillin production. J Bacteriol 53:329–341PubMedGoogle Scholar
  48. 48.
    Moyer AJ, Umberger EJ, Stubbs JJ (1940) Fermentation of concentrated solutions of glucose to gluconic acid. Improved process. Ind Eng Chem 32:1379–1383. doi: 10.1021/ie50370a022 CrossRefGoogle Scholar
  49. 49.
    Rolinson GN, Geddes AM (2007) The 50th anniversary of the discovery of 6-aminopenicillanic acid (6-APA). Int J Antimicrob Agent 29:3–8. doi: 10.1016/j.ijantimicag.2006.09.003 Google Scholar
  50. 50.
    Schmidt WH, Moyer AJ (1945) Penicillin I. Methods of assay. J Bacteriol 47:199–208Google Scholar
  51. 51.
    Scoutaris M (1996) “Moldy Mary” and the Illinois Fruit and Vegetable Company. Pharm Hist 38:175–177PubMedGoogle Scholar
  52. 52.
    Sheehan JC, Henery-Logan KR (1957) The total synthesis of penicillin V. J Am Chem Soc 79:1262–1263. doi: 10.1021/ja01562a063 CrossRefGoogle Scholar
  53. 53.
    Stubbs JJ, Lockwood LB, Roe ET, Tabenkin B, Ward GE (1940) Ketogluconic acids from glucose. Bacterial production. Ind Eng Chem 32:1626–1631. doi: 10.1021/ie50372a024 CrossRefGoogle Scholar
  54. 54.
    Swann JP (1983) The search for synthetic penicillin during World War II. Br J Hist Sci 16:154–190. doi: 10.1017/S0007087400026789 PubMedCrossRefGoogle Scholar
  55. 55.
    Tréfouël J, Tréfouël T, Nitti F, Bovet D (1935) Activité du p-amino-phenylsulfamide sur les infections streptococciques experimentales de la souris et du lapin. Compt Rend Soc Biol 120:756–758Google Scholar
  56. 56.
    Wainwright M, Swan HT (1986) G. C. Paine and the earliest surviving records of penicillin therapy. Med Hist 30:42–56PubMedGoogle Scholar
  57. 57.
    Wallace CD (1983) Control through disclosure legislation: foreign multinational enterprises in industrialized states. Int Comp Law Q 32:174–1412. doi: 10.1093/iclqaj/32.1.141 CrossRefGoogle Scholar
  58. 58.
    Wells PA, Lockwood LB, Stubbs JJ, Roe ET, Porges N, Gastrock EA (1939) Sorbose from sorbitol. Semiplant-scale production by Acetobacter suboxydans. Ind Eng Chem 31:1518–1521. doi: 10.1021/ie50360a018 CrossRefGoogle Scholar
  59. 59.
    Williams TI (1984) Howard Florey. Penicillin and after. Oxford University Press, OxfordGoogle Scholar
  60. 60.
    Wilson D (1976) In search of penicillin. AA Knopf, New YorkGoogle Scholar
  61. 61.
    Woodward RB (1972) Recent advances in the chemistry of natural products. In: Nobel lectures: chemistry 1963–1970. Elsevier, Amsterdam pp 100–121Google Scholar

Copyright information

© Society for Industrial Microbiology 2009

Authors and Affiliations

  1. 1.Department of Biological SciencesUniversity of PittsburghPittsburghUSA
  2. 2.PittsburghUSA

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