Antibiotics pp 189-228 | Cite as

Biosynthesis of β-Lactam Antibiotics

  • A. L. Demain
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 67 / 1)

Abstract

The discovery of penicillin by Fleming (1929) and its development by the Oxford group (Florey et al. 1949) began the antibiotic era. The success of this β-lactam antibiotic led the way for the development of all other antibiotics. As will be described later in this chapter, new and more effective β-lactam antibiotics are being discovered now, over 50 years after Fleming’s initial discovery.

Keywords

Lactose Nash Lactam Cefoxitin Penicillamine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aberhart DJ, Chu JY-R, Neuss N, Nash CH, Occolowitz J, Huckstep LL, De La Higuera N (1974) Retention of valine methyl hydrogens in penicillin biosynthesis. J Chem Soc Chem Commun: 564–565Google Scholar
  2. Aberhart DJ, Lin LJ (1974) Studies on the biosynthesis of ß-lactam antibiotics. 1. Stereo-specific synthesis of (2RS,3S)-[4,4,4- 2 H3]-, (2RS,3S)-[4- 3 H]-, (2RS,3R)-[4- 3 H]-, and (2RS,3S)-[4–13C]-valine. Incorporation of (2RS,3S)-[4-’3C]-valine into penicillin V. J Chem Soc Perkin Trans 1: 2320–2326CrossRefGoogle Scholar
  3. Abraham EP (1974) Biosynthesis and enzymic hydrolysis of penicillins and cephalosporins. University of Tokyo Press, TokyoGoogle Scholar
  4. Abraham EP (1977) ß-Lactam antibiotics and related substances. Jpn J Antibiot 30: 51–525Google Scholar
  5. Abraham EP, Huddleston JA, Jayatilake GS, O’Sullivan J, White RL (1980) Conversion of S-(L-a-aminoadipyl(-L-cysteinyl-D-valine to isopenicillin N in cell-free extracts of Cephalosporium acremonium. In: Gregory GI (ed) Recent advances in the chemistry of ßlactam antibiotics. Royal Society of Chemistry, London, pp 125–134Google Scholar
  6. Abraham EP, Newton GGF (1961) The structure of cephalosporin C. Biochem J 79: 377–393PubMedGoogle Scholar
  7. Abraham EP, Newton GGF, Warren SC (1965) Problems relating to the biosynthesis of peptide antibiotics. In: Vanek Z, Hostalek Z (eds) Biogenesis of antibiotic substances. Czech Acad Science, Prague, pp 169–194Google Scholar
  8. Adriaens P, Meesschaert B, Wuyts W, Vanderhaeghe H, Eyssen H (1975) Presence of 8-(La-aminoadipy1)-L-cysteinyl-D-valine in fermentations of Penicillium chrysogenum. Antimicrob Agents Chemother 8: 638–642PubMedGoogle Scholar
  9. Albers-Schönberg G, Arison BH, Kaczka E, Kahan FM, Kahan JS, Lago B, Maise WM, Rhodes RE, Smith JL (1976) Thienamycin. A new ß-lactam antibiotic. 3. Structure determination and biosynthetic data. Abstract 229, 16 th Intersci Conf Antimicrob Ag Chemother, ChicagoGoogle Scholar
  10. Aoki H, Sakai H-I, Kohsaka M, Konomi T, Hosoda J, Kubochi Y, Iguchi E, Imanaka H (1976) Nocardicin A, a new monocyclic ß-lactam antibiotic. 1. Discovery, isolation and characterization. J Antibiot (Tokyo) 29: 492–500Google Scholar
  11. Arnstein HRV, Clubb ME (1957) The biosynthesis of penicillin. Comparison of valine and hydroxyvaline as penicillin precursors. Biochem J 65: 618–627Google Scholar
  12. Arnstein HRV, Crawhall JC (1957) The biosynthesis of penicillin 6 A study of the mechanism of the formation of the thiazolidine-ß-lactam rings, using tritium-labelled cystine. Biochem J 67: 180–187PubMedGoogle Scholar
  13. Arnstein HRV, Grant PT ( 1954 a) The biosynthesis of penicillin. The incorporation of cystine into penicillin. Biochem J 57: 360–368Google Scholar
  14. Arnstein HRV, Grant PT ( 1954 b) The biosynthesis of penicillin. The incorporation of some amino acids into penicillin. Biochem J 57: 353–359Google Scholar
  15. Arnstein HRV, Margreiter H (1958) The biosynthesis of penicillin. 7. Further experiments on the utilization of L- and D-valine and the effect of cysteine and valine analogues on penicillin biosynthesis. Biochem J 68: 339–348PubMedGoogle Scholar
  16. Arnstein HRV, Morris D (1960) The structure of a peptide, containing a-aminoadipic acid, cysteine, and valine, present in the mycelium of Penicillium chrysogenum. Biochem J 76: 357–361PubMedGoogle Scholar
  17. Arnstein HRV, Artman N, Morris D, Toms EJ (1960) Sulfur-containing amino acids and peptides in the mycelium of Penicillium chrysogenum. Biochem J 76: 353–357PubMedGoogle Scholar
  18. Avanzini F, Valenti P (1980) Peptide presence constituted by a-aminoadipic acid (a-AAA) and valine in P. chrysogenum fermentation broth. Abstracts 6 th international ferm symp, London, Ontario, 20–25 July 1980, p 18Google Scholar
  19. Bahadur G, Baldwin JE, Field LD, Lehtonen EMM, Usher JJ, Vallijo CA, Abraham EP, White RL (1981) Direct 1H N.M.R. observation of the cell-free conversion of 8-(L-aaminoadipyl)-L-cysteinyl-D-valine and 8-(L-a-aminoadipyl)-L-cysteinyl-D-(—)-isoleucine into penicillins. J Chem Soc Chem Commun 917–919Google Scholar
  20. Baldwin JE, Wan TS (1979) Penicillin biosynthesis: a model for carbon and sulphur bond formation. J Chem Soc Chem Commun 249–250Google Scholar
  21. Baldwin JE, Wan TS (1981) Penicillin biosynthesis. Retention of configuration at C-3 of valine during its incorporation into the Arnstein tripeptide. Tetrahedron 37: 1589–1595CrossRefGoogle Scholar
  22. Baldwin JE, Lolliger J, Rastetter W, Neuss N, Huckstep LC, De La Higuera N (1973) Use of chiral isopropyl groups in biosynthesis. Synthesis of (2RS,3R))-[4- 13 C] valine. J Am Chem Soc 95: 3796–3797PubMedCrossRefGoogle Scholar
  23. Baldwin JE, Jung M, Singh P, Wan T, Haber S, Herchen S, Kitchin J, Demain AL, Hunt NA, Kohsaka M, Konomi T, Yoshida M (1980 a) Recent biosynthetic studies on ßlactam antibiotics. Philos Trans R Soc Lond B Biol Sci 298: 169–172Google Scholar
  24. Baldwin JE, Johnson BL, Usher JJ, Abraham EP, Huddleston JA, White RL (1980 b) Direct N.M.R. observation of cell-free conversion of (L-a-amino-6-adipyl)-L-cysteinyl-D-valine into isopenicillin N. J Chem Soc Chem Commun 1271–1273Google Scholar
  25. Baldwin JE, Chakravarti B, Jung M, Patel NJ, Singh PD, Usher JJ, Vallejo C (1981 a) On the possible role of the 3-methylene isomer of deacetoxycephalosporin C in the biosynthesis of cephalosporin. J Chem Soc Chem Commun 934–936Google Scholar
  26. Baldwin JE, Keeping JW, Singh PD, Vallejo CA (1981 b) Cell-free conversion of isopenicillin N into deacetoxycephalosporin C by Cephalosporium acremonium mutant M-0198. Biochem J 194: 649–651Google Scholar
  27. Baldwin JE, Singh PD, Yoshida M, Sawada, Demain AL (1980 c) Incorporation of 3H and ‘4C from [6a-3H] penicillin N into deacetoxycephalosporin C. Biochem J 186: 889–895Google Scholar
  28. Batchelor FR, Doyle FP, Nayler JHC, Rolinson GN (1959) Synthesis of penicillin: 6-aminopenicillanic acid in penicillin fermentations. Nature 183: 257–258PubMedCrossRefGoogle Scholar
  29. Bauer K (1970) Zur Biosynthese der Penicilline: Bildung von 5-(2-Aminoadipyl)-cysteinyl- valin in Extrakten von Penicillium chrysogenum. Z Naturforsch [B] 25: 1125–1129Google Scholar
  30. Behrens OK, Corse J, Jones RG, Kleinderer EC, Soper QF, Van Abelle FR, Larson LM, Sylvester JC, Haines WJ, Carter HE (1948) Biosynthesis of penicillins 2 Utilization of deuterophenylacetyl-N15-DL-valine in penicillin biosynthesis. J Biol Chem 175: 756–769Google Scholar
  31. Booth H, Bycroft BW, Wels CM, Corbett K, Maloney AP (1976) Application of 15N pulsed Fourier transformation nuclear magnetic resonance spectroscopy to biosynthetic studies; incorporation of L-[15N]-valine into penicillin G. J Chem Soc Chem Commun 110–111Google Scholar
  32. Bost PE, Demain AL (1977) Studies on the cell-free biosynthesis of ß-lactam antibiotics. Biochem J 162: 681–687PubMedGoogle Scholar
  33. Box SJ, Hood JD, Spear SR (1979) Four further antibiotics related to olivanic acid produced by Streptomyces olivaceus: fermentation, isolation, characterization, and biosynthetic studies. J Antibiot (Tokyo) 32: 1239–1247Google Scholar
  34. Brewer SJ, Boyle TT, Turner MK (1977 a) The carbamoylation of the 3-hydroxymethyl group of la-methoxy-7ß-(5-S-aminoadipamido)-3-hydroxymethylceph-3-em-4- carboxylic acid (desacetyl-7-methoxycephalosporin C) by homogenates of Streptomyces clavuligerus. Biochem Soc Trans. 5: 1026–1029Google Scholar
  35. Brewer SJ, Farthing JE, Turner MK (1977 b) The oxygenation of the 3-methyl group of 7ß(5-D-aminoadipamido)-3-methylceph-3-em-4-carboxylic acid (desacetoxycephalosporin C) by extracts of Acremonium chrysogenum. Biochem Soc Trans 5: 1024–1025Google Scholar
  36. Brewer SJ, Taylor PM, Turner MK (1980) An adenosine triphosphate-dependent carbamoyl-phosphate-3-hydroxymethylcephem O-carbamoyl-transferase from Streptomyces clavuligerus. Biochem J 185: 555–564PubMedGoogle Scholar
  37. Brown AG, Butterworth D, Cole M, Hanscomb G, Hood JD, Reading C, Rolinson GN (1976) Naturally occurring ß-lactamase inhibitors with antibacterial activity. J Antibiot (Tokyo) 29: 668–669Google Scholar
  38. Brown AG, Corbett DF, Eglington AJ, Howarth TT (1977) Structures of olivanic acid derivatives MM4450 and MM1392; two new, fused ß-lactams isolated from Streptomyces olivaceus. J Chem Soc Chem Commun 523–525Google Scholar
  39. Brown D, Evans JR, Fletton RA (1979) Structures of three novel ß-lactams isolated from Streptomyces clavuligerus. J Chem Soc Chem Commun 282–283Google Scholar
  40. Brundidge SP, Gaeta FCA, Hook DJ, Sapino C Jr, Elander RP, Morin RB (1980) Association of 6-oxo-piperidine-2-carboxylic acid with penicillin V production in Penicillium chrysogenum fermentations. J Antibiot (Tokyo) 33: 1348–1351Google Scholar
  41. Brunner R, Roehr M, Zinner M (1968) Zur Biosynthese des Penicillins. Hoppe-Seyler’s Z Physiol Chem 349: 95–103PubMedCrossRefGoogle Scholar
  42. Bycroft BS, Wels CM, Corbett K, Lowe DA (1975) Incorporation of [oc-2H] and [a-’H]-Lcystine into penicillin G and the location of the label using isotope exchange and 3H nuclear magnetic resonance. J Chem Soc Chem Commun 123Google Scholar
  43. Carver D, Godfrey OW (1974) Isolation of a mutant blocked in lysine catabolism and its effect on antibiotic synthesis in Streptomyces lipmanii. Annual meeting of the american society of microbiology [Abstr], 12–17 May 1974, Chicago, p 19Google Scholar
  44. Cassidy PJ (1981) Novel naturally occurring ß-lactam antibiotics–a review. Dev Ind Microbiol 22: 181–209Google Scholar
  45. Cassidy PG, Albers-Schonberg G, Goegelman RT, Miller T, Arison B, Stapley EO, Bernbaum J (1981) Epithienamycins. 2. Isolation and structure assignment. J Antibiot (Tokyo) 34: 637–648Google Scholar
  46. Chan JA, Huang F-C, Sih CJ (1976) The absolute configuration of the amino acids in S(a-aminoadipyl)-cysteinylvaline from Penicillium chrysogenum. Biochemistry 15: 177–180PubMedCrossRefGoogle Scholar
  47. Claridge CA, Luttinger RJ, Lein J (1963) Specificity of penicillin amidases. Proc Soc Exp Biol Med 113: 1008–1012PubMedGoogle Scholar
  48. Cole M (1966) Formation of 6-aminopenicillanic acid, penicillins, and penicillin acylase by various fungi. Appl Microbiol 14: 98–104PubMedGoogle Scholar
  49. Cole M, Batchelor FR (1963) Aminoadipylpenicillin in penicillin fermentations. Nature 198: 383–384PubMedCrossRefGoogle Scholar
  50. Cole M, Rolinson GN (1961) 6-Aminopenicillanic acid. 2. Formation of 6-aminopenicillanic acid by Emericellopsis minima ( Stolk) and related fungi. Proc R Soc Lond B Biol Sci 154: 490–497Google Scholar
  51. Corbett DF, Eglington AJ, Howarth TT (1977) Structure elucidation of MM17880, a new fused ß-lactam antibiotic isolated from Streptomyces olivaceus; a mild ß-lactam degradation reaction. J Chem Soc Chem Commun 953–954Google Scholar
  52. Craig JT, Tindall JB, Senkus M (1951) Determination of penicillin by using C13 isotope as a tracer. Anal Chem 23: 332–333CrossRefGoogle Scholar
  53. D’Amato RF, Pisano MA (1976) A chemically defined medium for cephalosporin C production by Paecilomyces persicinus. Antonie Van Leeunwenhoek J Microbiol Serol 42: 299–308CrossRefGoogle Scholar
  54. Demain AL (1956) Inhibition of penicillin formation by amino acid analogs. Arch Biochem Biophys 64: 74–79PubMedCrossRefGoogle Scholar
  55. Demain AL (1957) Inhibition of penicillin formation by lysine. Arch Biochem Biophys 67: 244–246PubMedCrossRefGoogle Scholar
  56. Demain AL (1959) The mechanism of penicillin biosynthesis. Adv Appl Microbiol 1:23–47 Demain AL (1963) L-Valine: a precursor of cephalosporin C. Biochem Biophys Res Cornmun 10: 45–48CrossRefGoogle Scholar
  57. Demain AL (1974) Biochemistry of penicillin and cephalosporin fermentations. Lloydia 37: 147–167PubMedGoogle Scholar
  58. Demain AL (1981) Biosynthetic manipulations in the development of ß-lactam antibiotics. In: Salton MRJ, Shockman GD (eds) ß-lactam antibiotics: mode of action, new developments and future prospects. Academic Press, New York, pp 567–583Google Scholar
  59. Dennen DW, Allen CC, Carver DD (1971) Arylamidase of Cephalosporium acremonium and its specificity for cephalosporin C. Appl Microbiol 21: 907–915PubMedGoogle Scholar
  60. Duncan M, Newton GGF (1970) Preparation and some properties of protoplasts from Cephalosporium sp. Acta Fac Med Univ Brun 37: 129–136Google Scholar
  61. Elson SW, Oliver RS (1978) Studies on the biosynthesis of clavulanic acid. Incorporation of 13C-labelled precursors. J Antibiot (Tokyo) 31: 586–592Google Scholar
  62. Erickson RC, Bennet RE (1965) Penicillin acylase activity of Penicillium chrysogenum. Appl Microbiol 13: 738–742PubMedGoogle Scholar
  63. Enriquez LA, Pisano MA (1979) Isolation and nature of intracellular alpha-aminoadipic acid-containing peptides from Paecilomyces persicinus P-10. Antimicrob Agents Chemother 16: 392–397Google Scholar
  64. Fawcett PA, Usher JJ, Abraham EP (1975) Behavior of tritium-labelled isopenicillin N and 6-aminopenicillanic acid as potential penicillin precursors in an extract of Penicillium chrysogenum. Biochem J 151: 741–746PubMedGoogle Scholar
  65. Fawcett PA, Usher JJ, Abraham EP ( 1976 a) Aspects of cephalosporin and penicillin biosynthesis. In: Macdonald KD (ed) Second international symposium on the genetics of industrial microorganisms. Academic Press, New York, pp 129–138Google Scholar
  66. Fawcett PA, Usher JJ, Huddleston JA, Bleaney RC, Nisbet JJ, Abraham EP (1976 b) Synthesis of S-(a-aminoadipyl)cysteinylvaline and its role in penicillin biosynthesis. Biochem J 157: 651–660Google Scholar
  67. Felix HR, Peter HH, Treichler HJ (1981) Microbiological ring expansion of penicillin N. J Antibiot (Tokyo) 34: 567–575Google Scholar
  68. Fleming A (1929) On the antibacterial action of a Penicillium, with special reference to their use in the isolation of B. influenzae. Br J Exp Pathol 10: 226–236Google Scholar
  69. Florey HW, Chain EB, Heatley NG, Jennings MA, Sanders AG, Abraham EP, Florey ME (1949) Antibiotics, vol 2. Oxford University Press, LondonGoogle Scholar
  70. Flynn EH, McCormick MH, Stamper MC, DeValeria H, Godzeski CW (1962) A new natural penicillin from Penicillium chrysogenum. J Am Chem Soc 84: 4594–4595CrossRefGoogle Scholar
  71. Friedrich CG, Demain AL (1978) Uptake and metabolism of a-aminoadipic acid by Penicillium chrysogenum. Wis 54–1255. Arch Microbiol 119: 43–47PubMedCrossRefGoogle Scholar
  72. Fujisawa Y, Kanzaki T (1975 a) Occurrence of a new cephalosporin in a culture broth of a Cephalosporium acremonium mutant. J Antibiot (Tokyo) 28: 372–378Google Scholar
  73. Fujisawa Y, Kanzaki T (1975 b) Role of acetyl CoA: deacetylcephalosporin C acetyltransferase in cephalosporin C biosynthesis by Cephalosporin acremonium. Agric Biol Chem 39: 2043–2048Google Scholar
  74. Fujisawa Y, Shirafuji H, Kida M, Nara K, Yoneda M, Kanzaki T (1973) New findings on cephalosporin C biosynthesis. Nature New Biol 246: 154–155PubMedGoogle Scholar
  75. Fujisawa Y, Kitano T, Kanyaki T (1975 a) Accumulation of deacetoxycephalosporin C by a deacetylcephalosporin C negative mutant of Cephalosporium acremonium. Agric Biol Chem 39: 2049–2055Google Scholar
  76. Fujisawa Y, Shirafuji H, Kida M, Nara K, Yoneda M, Kanzaki T (1975b) Accumulation of deacetylcephalosporin C by cephalosporin C negative mutants of Cephalosporium acremonium. Agric Biol Chem 39: 1295–1301CrossRefGoogle Scholar
  77. Fujisawa Y, Kikuchi M, Kanzaki T (1977) Deacetylcephalosporin C synthesis by cell-free extracts of Cephalosporium acremonium. J Antibiot (Tokyo) 30: 775–777Google Scholar
  78. Fukagawa Y, Kubo K, Ishikura T, Kuono K (1980) Deacetylation of PS-5, a new ß-lactam compound. 1. Microbial deacetylation of PS-5. J Antibiot (Tokyo) 33: 543–549Google Scholar
  79. Gatenback S, Brunsberg U (1968) Biosynthesis of penicillin. 1. Isolation of 6-aminopenicillanic acid acyltransferase from Penicillium chrysogenum. Acta Chem Scand 22: 1059–1061CrossRefGoogle Scholar
  80. Gordon M, Pan SC, Virgona A, Numerof P (1953) Biosynthesis of penicillin. I. Role of phenylacetic acid. Science 118: 43Google Scholar
  81. Goulden SA, Chattaway FW (1968) Lysine control of a-aminoadipate and penicillin synthesis in Penicillium chrysogenum. Biochem J 110: 55–56Google Scholar
  82. Hale CW, Miller GA, Kelly BK (1953) Hydrophilic penicillins produced by Penicillium chrysogenum. Nature 172: 545–546PubMedCrossRefGoogle Scholar
  83. Halliday WJ, Arnstein HRV (1956) The biosynthesis of penicillin. 4. The synthesis of benzylpenicillin by washed mycelium of Penicillium chrysogenum. Biochem J 64: 380–384PubMedGoogle Scholar
  84. Hashimoto M, Konomi T, Kamiya T (1976) Nocardicin A, a new monocyclic ß-lactam antibiotic. 2. Structure determination of nocardicins A and B. J Antibiot (Tokyo) 29: 890–901Google Scholar
  85. Higgens CE, Hamil RL, Sands TH, Hoehn MM, Davis NE, Nagarajan R, Boeck LD (1974) The occurrence of deacetoxycephalosporin C in fungi and streptomycetes. J Antibiot (Tokyo) 27: 298–300Google Scholar
  86. Hinnen A, Nuesch J (1976) Enzymatic hydrolysis of cephalosporin C by an extracellular acetylhydrolase of Cephalosporium acremonium. Antimicrob Agents Chemother 9: 824–830PubMedGoogle Scholar
  87. Hook DJ, Chang LT, Elander RP, Morin RB (1979) Stimulation of the conversion of penicillin N to cephalosporin by ascorbic acid, a-ketoglutarate, and ferrous ions in cell-free extracts of strains of Cephalosporium acremonium. Biochem Biophys Res Commun 87: 258–265PubMedCrossRefGoogle Scholar
  88. Hosada J, Konomi T, Tani N, Aoki H, Imanaka H (1977a) Isolation of new nocardicins from Nocardia uniformis subsp. tsuyamanensis. Agric Biol Chem 41: 2013–2020CrossRefGoogle Scholar
  89. Hosada J, Tani N, Konomi T, Ohsawa S, Aoki H, Imanaka H (1977b) Incorporation of 14C-amino acids into nocardicin A by growing cells. Agric Biol Chem 41: 2007–2012CrossRefGoogle Scholar
  90. Howarth TT, Brown AG, King TJ (1976) Clavulanic acid, a novel ß-lactam isolated from Streptomyces clavuligerus; X-ray crystal structure analysis. J Chem Soc Chem Cornmun: 266–267Google Scholar
  91. Huang F-C, Chan JA, Sih CJ, Fawcett P, Abraham EP (1975) The nonparticipation of a,ßdehydrovalinyl intermediates in the formation of 8-(L-a-aminoadipyl)-L-cysteinyl-D-valine. J Am Chem Soc 97: 3858–3859PubMedCrossRefGoogle Scholar
  92. Huber FM, Baltz RH, Caltrider PG (1968) Formation of desacetylcephalosporin C in cephalosporin C fermentation. Appl Microbiol 16: 1011–1014PubMedGoogle Scholar
  93. Huddleston JA, Abraham EP, Young DW, Morecombe DJ, Sen PK (1978) The stereochem- istry of ß-lactam formation in cephalosporin biosynthesis. Biochem J 169: 705–707PubMedGoogle Scholar
  94. Imada A, Nozaki Y, Kintaka K, Okonogi K, Kitano K, Harada S (1980) C-19393 and H2, new carbapenem antibiotics. 1. Taxonomy of the producing strain, fermentation, and antibacterial properties. J Antibiot (Tokyo) 33: 1417–1424Google Scholar
  95. Imada A, Kitano K, Kintaka K, Muroi A, Asai M (1981) Sulfazecin and isosulfazecin, novel ß-lactam antibiotics of bacterial origin. Nature 289: 590–591PubMedCrossRefGoogle Scholar
  96. Inamine E, Birnbaum J (1972) Cephamycin C biosynthesis: isotope incorporation studies. Abstr Annual meeting of the american society of microbiology, 23–28 April 1972, Philadelphia, p 12Google Scholar
  97. Jayatilake S, Huddleston JA, Abraham EP (1981) Conversion of isopenicillin N into penicil- lin N in cell-free extracts of Cephalosporium acremonium. Biochem J 194: 645–647PubMedGoogle Scholar
  98. Kahan JS, Kahan FM, Goegelman R, Currie SA, Jackson M, Stapley EO, Miller TW, Miller AK, Hendlin D, Mochales S, Hernandez S, Woodruff HB, Birnbaum J (1979) Thienamycin. A new ß-lactam antibiotic. 1. Discovery, taxonomy, isolation, and physical properties. J Antibiot (Tokyo) 32: 1–12Google Scholar
  99. Kanzaki T, Fujisawa Y (1976) Biosynthesis of cephalosporin. Adv Appl Microbiol 20: 159–201PubMedCrossRefGoogle Scholar
  100. Kanzaki T, Fukita T, Shirafuji H, Fujisawa Y, Kitano K (1974) Occurrence of a 3-methylthiomethylcephem derivative in a culture broth of Cephalosporium mutant. J Antibiot (Tokyo) 27: 361–362Google Scholar
  101. Kanzaki T, Fukita T, Kitano K, Katamoto K, Nara K, Nakao Y (1976) Occurrence of a novel cephalosporin compound in the culture broth of a Cephalosporium acremonium mutant. J Ferment Technol 54: 720–725Google Scholar
  102. Kato K (1953) Occurrence of penicillin-nucleus in culture broths. J Antibiot Ser (Tokyo) 6: 130–136Google Scholar
  103. Kern BA, Hendlin D, Inamine E (1980) L-lysine e-aminotransferase involved in cephamycin C synthesis in Streptomyces lactamdurans. Antimicrob Agents Chemother 17: 679–685PubMedGoogle Scholar
  104. Kitano K (1977) Studies on the production of ß-lactam antibiotics. Ph. D. thesis, Osaka University, Osaka, JapanGoogle Scholar
  105. Kitano K, Kintaka K, Suzuki S, Katamoto K, Nara K, Nakao Y (1974) Production of cephalosporin antibiotics by strains belonging to the genera Arachnomyces, Anixiopis, and Spiroidium. Agric Biol Chem 38: 1761–1762CrossRefGoogle Scholar
  106. Kitano K, Kintaka K, Katamoto K, Nara K, Nakao Y (1975 a) Occurrence of 6-aminopenicillanic acid in culture broths of strains belonging to the genera Thermoascus, Gymnoscus, Polypaecilum, and Malbranchea. J Ferment Technol 53: 339–346Google Scholar
  107. Kitano K, Kintaka K, Suzuki S, Katamoto K, Nara K, Nakao Y (1975 b) Screening of microorganisms capable of producing ß-lactam antibiotics. J Ferment Technol 53: 327–338Google Scholar
  108. Kitano K, Kintaka K, Suzuki S, Katamoto K, Nara K, Nakao Y (1976 a) Screening of microorganisms capable of producing ß-lactam antibiotics from n-paraffins. J Ferment Technol 54: 683–695Google Scholar
  109. Kitano K, Fujisawa Y, Katamoto K, Nara K, Nakao Y (1976b) Occurrence of 7ß-(4-carboxybutanamido)-cephalosporin compounds in the culture broth of some strains of the genus Cephalosporium. J Ferment Technol 54: 712–719Google Scholar
  110. Kitano K, Kintaka K, Suzuki S, Katamoto K, Nara K, Nakao Y (1976c) A novel penicillinGoogle Scholar
  111. produced by strains of the genus Paecilomyces. J Ferment Technol 54:705–711Google Scholar
  112. Kluender H, Bradley CH, Sih CJ, Fawcett P, Abraham EP (1973) Synthesis and incorporation of (2S,3S) [4–13C]-valine into ß-lactam antibiotics. J Am Chem Soc 95: 6149–6150CrossRefGoogle Scholar
  113. Kocecny J, Felber E, Gruner J (1973) Kinetics of the hydrolysis of cephalosporin C. J Antibiot (Tokyo) 26: 135–141Google Scholar
  114. Kohsaka M, Demain AL (1976) Conversion of penicillin N to cephalosporin(s) by cell-free extracts of Cephalosporium acremonium. Biochem Biophys Res Commun 70: 465–473PubMedCrossRefGoogle Scholar
  115. Konomi T, Herchen S, Baldwin JE, Yoshida M, Hunt NA, Demain AL (1979) Cell-free conversion of 6-(L-a-aminoadipyl)-L-cysteinyl-D-valine to an antibiotic with the properties of isopenicillin N in Cephalosporium acremonium. Biochem J 184: 427–430PubMedGoogle Scholar
  116. Konomi T, Herchen S, Baldwin JE, Yoshida M, Hunt NA, Demain AL (1979) Cell-free conversion of 6-(L-a-aminoadipyl)-L-cysteinyl-D-valine to an antibiotic with the properties of isopenicillin N in Cephalosporium acremonium. Biochem J 184: 427–430PubMedGoogle Scholar
  117. Konomi T, Herchen S, Baldwin JE, Yoshida M, Hunt NA, Demain AL (1979) Cell-free conversion of 6-(L-a-aminoadipyl)-L-cysteinyl-D-valine to an antibiotic with the properties of isopenicillin N in Cephalosporium acremonium. Biochem J 184: 427–430PubMedGoogle Scholar
  118. Lemke PA, Nash CH (1972) Mutations that affect antibiotic synthesis by Cephalosporium acremonium. Can J Microbiol 18: 255–259PubMedCrossRefGoogle Scholar
  119. Liersch M, Nuesch J, Treichler HJ (1976) Final steps in the biosynthesis of cephalosporin C. In: Macdonald KD (ed) Second international symposium on the genetics of industrial microorganisms. Academic Press, New York, pp 179–195Google Scholar
  120. Loder PB (1972) Postepy Hig Med Dosw 26: 493–500PubMedGoogle Scholar
  121. Loder PB, Abraham EP (1971 a) Isolation and nature of intracellular peptides from a cephalosporin C-producing Cephalosporium sp. Biochem J 123: 471–476Google Scholar
  122. Loder PB, Abrahm AP (1971 b) Biosynthesis of peptides containing a-aminoadipic acid and cysteine in extracts of a Cephalosporium sp. Biochem J 123: 477–482Google Scholar
  123. Maeda K, Takahashi S, Sezaki M, Iinuma K, Naganawa H, Kondo S, Ohno M, Umezawa H (1977) Isolation and structure of a ß-lactamase inhibitor from Streptomyces. J Antibiot (Tokyo) 30: 770–772Google Scholar
  124. Makins JF, Holt G, Macdonald KD (1980) Co-synthesis of penicillin following treatment of mutants of Aspergillus nidulans impaired in antibiotic production with lytic enzymes. J Gen Microbiol 119: 397PubMedGoogle Scholar
  125. Mehta RJ, Speth JL, Nash CH (1979) Lysine stimulation of cephalosporin C synthesis in Cephalosporium acremonium. Eur J Appl Microbiol Biotechnol 8: 177–182CrossRefGoogle Scholar
  126. Meesschaert B, Adriaens P, Eyssen H (1980) Studies on the biosynthesis of isopenicillin N with a cell-free preparation of Penicillium chrysogenum. J Antibiot (Tokyo) 33: 722–730Google Scholar
  127. Miller RD, Huckstep LL, McDermott JP, Queener SW, Kukolja S, Spry DO, Elzey TK, Lawrence SM, Neuss N (1981) High performance liquid chromatography (HPLC) of natural products. 4. Isolation of a new cepham derivative from the broth of Cephalosporium acremonium and its role in the biosynthesis of cephalosporin C in the cell-free system. J Antibiot (Tokyo) 34: 984–993Google Scholar
  128. Morecombe DJ, Young DW (1975) Synthesis of chirally labeled cysteines and the steric origin of C(5) in penicillin biosynthesis. J Chem Soc Chem Commun: 198–199Google Scholar
  129. Morin RB, Jackson BG, Mueller RA, Lavagnino ER, Scanlon WB, Andrews SL (1963) Chemistry of cephalosporin antibiotics. 3. Chemical correlation of penicillin and cephalosporin antibiotics. J Am Chem Soc 85: 1896–1897Google Scholar
  130. Murao S (1955) Studies on penicillin-amidase. 2. Research on conditions of producing penicillin amidase. J Agric Chem Soc Jpn 29: 400–403Google Scholar
  131. Nagarajan R, Boeck LD, Gorman M, Hamill RL, Higgens CH, Hoehn MM, Stark WM, Whitney JG (1971) ß-Lactam antibiotics from Streptomyces. J Am Chem Soc 93: 2308–2310PubMedCrossRefGoogle Scholar
  132. Nakayama M, Kimura S, Tanabe S, Mizoguchi T, Watanabe I, Mori T, Miyahara K, Kawasaki T (1981) Structures and absolute configuration of carpetimycins A and B. J Antibiot (Tokyo) 34: 818–823Google Scholar
  133. Nash CH, De La Higuera N, Neuss N, Lemke PA (1974) Application of biochemical genetics to the biosynthesis of ß-lactam antibiotics. Dev Ind Microbiol 15: 114–123Google Scholar
  134. Neuss N, Nash CH, Baldwin JE, Lemke PA, Grutzner JB (1973) Incorporation of (2RS,3R)[4–13C] valine into cephalosporin C. J Am Chem Soc 95: 3797PubMedCrossRefGoogle Scholar
  135. Neuss N, Miller RD, Affolder CA, Nakatsukosa W, Mabe J, Huckstepp LL, De la Higuera N, Hunt AH, Occolowitz J, Gilham JH (1980) High performance liquid chromatography (HPLC) of natural products. 3. Isolation of new tripeptides from the fermentation broth of P. chrysogenum. Helv Chim Acta 63: 1119–1129CrossRefGoogle Scholar
  136. Neuss N, Nash CH, Lemke PA, Grutzner JB (1971) The use of i3C nmr. (CMR) spectroscopy in biosynthetic studies of ß-lactam antibiotics. 1. The incorporation of [1–13C]- and [2–13C]-sodium acetate and DL-[1–13C]- and DL-[2–13]-valine into cephalosporin C. Proc R Soc S Lond B Biol Sci 179: 2337–2339Google Scholar
  137. Newton GGF, Abraham EP (1955) Cephalosporin C, a new antibiotic containing sulfur and D-a-aminoadipic acid. Nature 175: 548PubMedCrossRefGoogle Scholar
  138. Okamura K, Hirata S, Okumura Y, Fukagawa Y, Shimanchi Y, Kouno K, Ishikura T, Lein J (1978) PS-5, a new ß-lactam antibiotic from Streptomyces. J Antibiot (Tokyo) 31: 480–482Google Scholar
  139. Osono T, Watanabe S, Saito T, Gushima H, Murakami K, Tokohashi I, Yamaguchi H, Sasaki T, Susaki K, Tokamera S, Miyoshi T, Oka Y (1980) Oganomycins, new 7methoxycephalosporins produced by precursor fermentation with heterocyclic thiols. J Antibiot (Tokyo) 33: 1074–1078Google Scholar
  140. O’Sullivan J, Abraham EP (1980) The conversion of cephalosporins to 7 a-methoxycephalo- sporins by cell-free extracts of Streptomyces clavuligerus. Biochem J 186: 613–616PubMedGoogle Scholar
  141. O’Sullivan J, Bleaney RC, Huddleston JA, Abraham EP (1979 a) Incorporation of 3H from 8-(L-a-amino-[4,5–3H]adipyl)-L-cysteinyl-D-[4,4–3H] valine into isopenicillin N. Biochem J 184: 421–426Google Scholar
  142. O’Sullivan J, Aplin RT, Stevens CM, Abraham EP ( 1979 b) Biosynthesis of 7-a-methoxycephalosporin. Incorporation of molecular oxygen. Biochem J 179: 47–52Google Scholar
  143. O’Sullivan J, Gillum AM, Aklonis CA, Souser ML, Sykes RB (1982) Biosynthesis of monobactam compounds; origin of the carbon atoms in the ß-lactam ring. Antimicrob. Agents Chemother 21: 558–564Google Scholar
  144. Pisano MA, Velozzi EM (1974) Production of cephalosporin C by Paecilomyces persicinus P-10. Antimicrob Agents Chemother 6: 447–451PubMedGoogle Scholar
  145. Pruess DL, Johnson MJ (1967) Penicillin acyltransferase in Penicillium chrosygenum. J Bacteriol 94: 1502–1508PubMedGoogle Scholar
  146. Queener SW, Capone JJ, Radue AB, Nagarajan R (1974) Synthesis of deacetoxycephalosporin C by a mutant of Cephalsporium acremonium. Antimicrob Agents Chemother 6: 334–337PubMedGoogle Scholar
  147. Reading C, Cole M (1977) Clavulanic acid: a beta-lactamase-inhibiting beta-lactam from Streptomyces clavuligerus. Antimicrob Agents Chemother 11: 852–857PubMedGoogle Scholar
  148. Rosi D, Droze ML, Kuhrt MF, Terminello L, Came PE, Daum SJ (1981) Mutants of Streptomyces cattleya producing N-acetyl and dehydro carbopenems related to thienamycin. J Antibiot (Tokyo) 34: 341–343Google Scholar
  149. Sawada Y, Hunt NA, Demain AL (1979) Further studies on microbiological ring expansion of penicillin N. J Antibiot (Tokyo) 32: 1303–1310Google Scholar
  150. Sawada Y, Baldwin JE, Singh PD, Solomon NA, Demain AL (1980 a) Cell-free cyclization of 8-(L-a-aminoadipyl)-L-cysteinyl-D-valine to isopenicillin N. Antimicrob Agents Chemother 18: 465–470Google Scholar
  151. Sawada Y, Solomon NA, Demain AL (1980 b) Stimulation of the cell-free ß-lactam ring expansion reaction by sonication and Triton X-100. Biotechnol Lett 2: 43–48Google Scholar
  152. Sebek OK (1953) Biosynthesis of Cl’-labelled benzylpenicillin. Proc Soc Exp Biol Med 84: 170–172PubMedGoogle Scholar
  153. Shirafuji H, Fujisawa Y, Kida M, Kanzaki T, Yoneda M (1979) Accumulation of tripeptide derivatives by mutants of Cephalosporium acremonium. Agric Biol Chem 43: 155–160CrossRefGoogle Scholar
  154. Somerson NL, Demain AL, Nunheimer TD (1961) Reversal of lysine inhibition of penicillin production by a-aminoadipic acid. Arch Biochem Biophys 93: 238–241CrossRefGoogle Scholar
  155. Spencer B (1968) The biosynthesis of penicillins-acylation of 6-amino-penicillanic acid. Biochem Biophys Res Commun 31: 170–175PubMedCrossRefGoogle Scholar
  156. Spencer B, Maung C (1970) Multiple activities of penicillin acyltransferase of Penicillium chrysogenum. Biochem J 118: 29–30Google Scholar
  157. Stapley EO, Jackson M, Hernandez S, Zimmerman SB, Currie SA, Mochalis S, Mahta JM, Woodruff HB, Hendlin D (1972) Cephamycins, a new family of ß-lactam antibiotics. 1. Production by actinomycetes, including Streptomyces lactamdurans sp. n. Antimicrob Agents Chemother 2: 122–131PubMedGoogle Scholar
  158. Stapley EO, Birnbaum J, Miller AK, Wallick H, Hendlin D, Woodruff HB (1979) Cefoxitin and cephamycins: microbiological studies. Rev Inf Dis 1: 73–87CrossRefGoogle Scholar
  159. Stapley EO, Cassidy P, Tunac J, Monaghan RL, Jackson M, Hernandez S, Zimmerman SB, Mahta JM, Currie SA, Dovryt D, Hendlin D (1981) Epithienamycins — novel ß-lactams related to thienamycin. I. Production and antibacterial activity. J Antibiot (Tokyo) 34: 628–636Google Scholar
  160. Stauffer JF, Schwartz LJ, Brady CW (1966) Problems and progress in a strain selection program with cephalosporin-producing fungi. Dev Ind Microbiol 7: 104–113Google Scholar
  161. Stevens CM, Vohra P, Inamine E, Roholt OA Jr (1953) Utilization of sulfur compounds for the biosynthesis of penicillins. J Biol Chem 205: 1001–1006PubMedGoogle Scholar
  162. Stevens CM, Vohra P, Delong CW (1954) Utilization of valine in the biosynthesis of penicillins. J Biol Chem 211: 297–300PubMedGoogle Scholar
  163. Stevens CM, Inamine E, Delong CW (1956) The rates or incorporation of L-cysteine and D- and L-valine in penicillin biosynthesis. J Biol Chem 219: 405–409PubMedGoogle Scholar
  164. Stevens CM, Delong CW (1958) Valine metabolism and penicillin biosynthesis. J Biol Chem 230: 991–999PubMedGoogle Scholar
  165. Stevens CM, Abraham EP, Huang F-C, Sih CJ (1975) Incorporation of molecular oxygen at C-17 of cephalosporin C during its biosynthesis. Fed Proc 34: 625Google Scholar
  166. Stirling I, Elson SW (1979) Studies on the biosynthesis of clavulanic acid. 2. Chemical degradations of i4C-labelled clavulinic acid. J Antibiot (Tokyo) 32: 1125–1129Google Scholar
  167. Sykes RB, Cimarusti CM, Bonner DP, Bush K, Floyd DM, Georgopapadakou NH, Koster WH, Liu WC, Parker WL, Principe PA, Rathnum ML, Slusarchyk WA, Trejo WH, Wells JS (1981) Monocyclic ß-lactam antibiotics produced by bacteria. Nature 291: 489–491PubMedCrossRefGoogle Scholar
  168. Turner MK, Farthing JE, Brewer SJ (1978) The oxygenation of [3-methyl-3H] desacetoxycephalosporin C [7ß-(5-u-aminoadipamido)-3-methylceph-3-em-4-carboxylic acid] to [3-hydroxymethyl- 3 H] desacetylcephalosporin C by 2-oxoglutarate-linked dioxygenases from Acremonium chrysogenum and Streptomyces clavuligerus. Biochem J 173: 839–850PubMedGoogle Scholar
  169. Traxler P, Treichler HJ, Nuesch J (1975) Synthesis of N-acetyldeacetoxycephalosporin C by a mutant of Cephalosporium acremonium. J Antibiot (Tokyo) 28: 605–606Google Scholar
  170. Troonen H, Roelants P, Boon B (1976) RIT 2214, a new biosynthetic penicillin produced by a mutant of Cephalosporium acremonium. J Antibiot (Tokyo) 29: 1258–1267Google Scholar
  171. Trown PW, Abraham EP, Newton GGF, Hale CW, Miller GA (1962) Incorporation of acetate into cephalosporin C. Biochem J 84: 157–166PubMedGoogle Scholar
  172. Trown PW, Smith B, Abraham EP (1963 a) Biosynthesis of cephalosporin C from amino acids. Biochem J 86: 284–291Google Scholar
  173. Trown PW, Sharp M, Abraham EP (1963 b) a-Oxoglutarate as a precursor of the D-aaminoadipic residue in cephalosporin C. Biochem J 86: 280–284Google Scholar
  174. Vanderhaeghe H, Claesen M, Vlietinck A, Parmentier G (1968) Specificity of penicillin acy- lase of Fusarium and of Penicillium chrysogenum. Appl Microbiol 16: 1557–1563Google Scholar
  175. Warren SC, Newton GGF, Abraham EP (1967 a) Use of a-aminoadipic acid for the biosynthesis of penicillin N and cephalosporin C by a Cephalosporium sp. Biochem J 103: 891–901Google Scholar
  176. Warren SC, Newton GGF, Abraham EP (1967b) The role of valine in the biosynthesis of penicillin N and cephalosporin C by a Cephalosporium sp. Biochem J 103: 902–912PubMedGoogle Scholar
  177. Whitney JD, Brannon DR, Mabe JA, Wicker KJ (1972) Incorporation of labeled precursors into A16886B, a novel ß-lactam antibiotic produced by Streptomyces clavuligerus. Antimicrob Agents Chemother 1: 247–251PubMedGoogle Scholar
  178. Wolff EC, Arnstein HRV (1960) The metabolism of 6-aminopenicillanic acid and related compounds by Penicillium chrysogenum and its possible significance for penicillin biosynthesis. Biochem J 76: 375–381PubMedGoogle Scholar
  179. 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 Acid Sci USA 75: 6253–6257Google Scholar
  180. Young DW, Morecombe DJ, Sen PK (1977) The stereochemistry of ß-lactam formation in penicillin biosynthesis. Eur J Biochem 75: 133–147PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1983

Authors and Affiliations

  • A. L. Demain

There are no affiliations available

Personalised recommendations