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Mechanisms of Resistance to Aminoglycoside Antibiotics

  • H. Umezawa
  • S. Kondo
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 62)

Abstract

During the early 1950s when strongly resistant organisms had not yet appeared, the chemotherapy of most bacterial infections was assumed to be possible. However, tubercle bacilli soon became resistant to streptomycin and new active agents were required for the treatment of tuberculosis. At that time, Umezawa discovered the aminoglycoside antibiotic, kanamycin, in the search for new water-soluble basic antibiotics (H. Umezawa et al. 1957). Kanamycin was evaluated as an effective agent for the treatment of infections with resistant staphylococci and streptomycin-resistant tuberculosis, and later for the treatment of infections with resistant gram-negative bacteria. However, after widespread use of the antibiotic, in 1965 kanamycin-resistant strains appeared in patients, although at a frequency of less than 5%. Therefore, Umezawa undertook studies on the biochemical mechanisms of resistance to aminoglycoside antibiotics (H. Umezawa et al. 1967 a, b). The results of these studies suggested structures which would be active against resistant strains and many derivatives of aminoglycoside antibiotics were synthesized. Among these, 3’,4’-dideoxykanamycin B (dibekacin) (H. Umezawa et al. 1971) was useful in the treatment of infections with resistant gram-positive and -negative bacteria, including pseudomonas, and was marketed in 1975.

Keywords

Resistant Strain Antimicrob Agent Resistant Bacterium Aminoglycoside Antibiotic Solid Matrix Support 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Abe Y, Nakagawa S, Fujisawa K, Naito T, Kawaguchi H (1977) Aminoglycoside antibiotics. XI. Synthesis and activity of 4’-deoxykanamycin B. J Antibiot (Tokyo) 30:1004–1007Google Scholar
  2. Akiba T, Koyama K, Isshiki Y, Kimura S, Fukushima T (1960) On the mechanism of the development of multiple drug resistance clones of Shigella (in Japanese). Nippon Iji Shimpo 1866:46–50Google Scholar
  3. Benveniste R, Davies J (1971a) R-factor mediated gentamicin resistance: a new enzyme which modifies aminoglycoside antibiotics. FEBS Lett 14:293–296PubMedGoogle Scholar
  4. Benveniste R, Davies J (1971b) Enzymatic acetylation of aminoglycoside antibiotics by Escherichia coli carrying an R-factor. Biochemistry 10:1787–1796PubMedGoogle Scholar
  5. Benveniste R, Davies J (1973) Aminoglycoside antibiotic-inactivating enzymes in Actinomy-cetes similar to those present in clinical isolates of antibiotic-resistant bacteria. Proc Natl Acad Sci USA 70:2276–2280PubMedGoogle Scholar
  6. Benveniste R, Yamada T, Davies J (1970) Enzymatic adenylylation of streptomycin and spectinomycin by R-factor-resistant Escherichia coli. Infect Immun 1:109–119PubMedGoogle Scholar
  7. Brzezinska M, Davies J (1973) Two enzymes which phosphorylate neomycin and kanamy-cin in Escherichia coli strains carrying R factors. Antimicrob Agents Chemother 3:266–269PubMedGoogle Scholar
  8. Brzezinska M, Benveniste R, Davies J, Daniels PJL, Weinstein J (1972) Gentamicin resistance in strains of Pseudomonas aeruginosa mediated by enzymatic N-acetylation of the deoxystreptamine moiety. Biochemistry 11:761–765PubMedGoogle Scholar
  9. Chevereau M, Daniels PJL, Davies J, LeGoffic F (1974) Aminoglycoside resistance in bacteria mediated by gentamicin acetyltransferase II, an enzyme modifying the 2’-amino group of aminoglycoside antibiotics. Biochemistry 13:598–603PubMedGoogle Scholar
  10. Cochran TG, Abraham DJ (1972) Stereochemistry and absolute configuration of the antibiotic spectinomycin: an X-ray diffraction study. J Chem Soc Chem Commun 494–495Google Scholar
  11. Courvalin P, Weisblum B, Davies J (1977) Aminoglycoside-modifying enzyme of an antibiotic-producing bacterium acts as a determinant of antibiotic resistance in Escherichia coli. Proc Natl Acad Sci USA 74:999–1008PubMedGoogle Scholar
  12. Culbertson TP, Watson DR, Haskell TH (1973) 5”-Amino-5”-deoxybutirosin, a new semisynthetic aminoglycoside antibiotic. J Antibiot (Tokyo) 26:790–793Google Scholar
  13. Daniels PJL, Weinstein J, Tkach RW, Morton J (1974a) Gentamicin derivatives modified at the 2”-position. The preparation of 2”-epi-gentamicin C1 and 2”-deoxy gentamicin C2. J Antibiot (Tokyo) 27:150–154Google Scholar
  14. Daniels PJL, Weinstein J, Nagabhushan TL (1974b) The syntheses of l-N-[(S-4-amino-2-hydroxybutyryljgentamicin C1 and l-N-[(S)-3-amino-2-hydroxypropionyl]gentamicin C1. J Antibiot (Tokyo) 27:889–893Google Scholar
  15. Daniels PJL, Cooper AB, McCombie SW, Nagabhushan TL (1979) Some recent advances in the chemistry of antibiotics of the gentamicin series. Jpn J Antibiot 32:S195-S204PubMedGoogle Scholar
  16. Davies J, O’Connor S (1978) Enzymatic modification of aminoglycoside antibiotics: 3-N-acetyltransferase with broad specificity that determines resistance to the novel aminoglycoside apramycin. Antimicrob Agents Chemother 14:69–72PubMedGoogle Scholar
  17. Davies J, Smith DI (1978) Plasmid-determined resistance to antimicrobial agents. Ann Rev Microbiol 32:469–518Google Scholar
  18. Deushi T, Iwasaki A, Kamiya K, Kunieda T, Mizoguchi T, Nakayama M, Itoh H, Mori T, Oda T (1979a) A new broad-spectrum aminoglycoside antibiotic complex, spor-aricin. I. Fermentation, isolation and characterization. J Antiobiot (Tokyo) 32:173–179Google Scholar
  19. Deushi T, Nakayama M, Watanabe I, Mori T, Naganawa H, Umezawa H (1979b) A new broad-spectrum aminoglycoside antibiotic complex, sporaricin. III. The structures of sporaricins A and B. J Antibiot (Tokyo) 32:187–192Google Scholar
  20. Deushi T, Iwasaki A, Kamiya K, Mizoguchi T, Nakayama M, Itoh H, Mori T (1979c) New aminoglycoside antibiotics, sannamycin. J Antibiot (Tokyo) 32:1061–1065Google Scholar
  21. Doi O, Ogura M, Tanaka N, Umezawa H (1968a) Inactivation of kanamycin, neomycin, and streptomycin by enzymes obtained in cells of Pseudomonas aeruginosa. Appl Microbiol 16:1276–1281PubMedGoogle Scholar
  22. Doi O, Miyamoto M, Tanaka N, Umezawa H (1968b) Inactivation and phosphorylation of kanamycin by drug-resistant Staphylococcus aureus. Appl Microbiol 16:1282–1284PubMedGoogle Scholar
  23. Doi O, Kondo S, Tanaka N, Umezawa H (1969) Purification and properties of kanamycin-phosphorylating enzyme from Pseudomonas aeruginosa. J Antibiot (Tokyo) 22:273–282Google Scholar
  24. Egan RS, Stanaszek RS, Cirovic M, Mueller SL, Tadanier J, Martin JR, Collum P, Goldstein AW, Devault RL, Sinclair AC, Fager EE, Mitscher LA (1977) Fortimicins A and B, new aminoglycoside antibiotics. III. Structural identification. J Antibiot (Tokyo) 30:552–563Google Scholar
  25. Fu KP, Neu HC (1978) Activity of 5-episisomicin compared with that of other aminoglycosides. Antimicrob Agents Chemother 14:194–200PubMedGoogle Scholar
  26. Fukasawa K, Sakurai H, Shimizu S, Naganawa H, Kondo S, Kawabe H, Mitsuhashi S (1980) 3”-Phosphoryldihydrostreptomycin produced by the inactivating enzyme of Er-winia carotovora. J Antibiot (Tokyo) 33:122–123Google Scholar
  27. Haas M, Biddlecome S, Davies J, Luce CE, Daniels PJL (1976) Enzymatic modification of aminoglycoside antibiotics: a new 6’-N-acetylating enzyme from Pseudomonas aeruginosa isolate. Antimicrob Agents Chemother 9:945–950PubMedGoogle Scholar
  28. Hanessian S, Yatele J (1980) Aminoglycoside antibiotics. 4’-Deoxyneomycin and 4’-deoxy-paromamine. J Antibiot (Tokyo) 33:675–678Google Scholar
  29. Hanessian S, Massé R, Capmeau M (1977) Aminoglycoside antibiotics: synthesis of 5”-amino-5”-deoxyneomycin and 5”-amino-5”-deoxyparomomycin. J Antibiot (Tokyo) 30:893–896Google Scholar
  30. Hirayama N, Shirahata K, Ohashi Y, Sasada Y, Martin JR (1978) Structure of fortimicin B. Acta Crystallogr Sect B Struct Crystallogr Cryst Chem B34:2648–2650Google Scholar
  31. Hsiang MW, White TJ, Davies JE (1978) NH2-Terminal sequence of the aminoglycoside acetyltransferase (3)-I mediated by plasmid RIP 135. FEBS Lett 92:97–99PubMedGoogle Scholar
  32. Hori M, Umezawa H (1967) Miscoding activities of biologically inactivated kanamycins. J Antiobiot (Tokyo) A20:386–387Google Scholar
  33. Iida T, Sato M, Matsubara I, Mori Y, Shirahata K (1979) The structures of fortimicins C, D, and KE. J Antibiot (Tokyo) 32:1273–1279Google Scholar
  34. Ikeda D, Tsuchiya T, Umezawa S, Umezawa H, Hamada M (1973a) Synthesis of 3’,4’-dideoxybutirosin B. J Antibiot (Tokyo) 26:307–309Google Scholar
  35. Ikeda D, Tsuchiya T, Umezawa S, Umezawa H (1973b) Synthesis of 3’-deoxyribostamycin. J Antibiot (Tokyo) 26:799–801Google Scholar
  36. Ikeda D, Nagaki F, Umezawa S, Tsuchiya T, Umezawa H (1975) Synthesis of 3’-deoxy-butirosin B. J Antibiot (Tokyo) 28:616–618Google Scholar
  37. Ikeda D, Miyasaka T, Yoshida K, Iinuma K, Kondo S, Umezawa H (1979) The chemical conversion of gentamine C1a into gentamine C2 and its 6’-epimer. J Antibiot (Tokyo) 32:1357–1359Google Scholar
  38. Inouye S, Ohba K, Shomura T, Kojima M, Tsuruoka T, Yoshida J, Kato N, Ito M, Amano S, Omoto S, Ezaki N, Ito T, Niida T, Watanabe K (1979) A novel aminoglycoside antibiotic, substance SF-2052. J Antibiot (Tokyo) 32:1354–1356Google Scholar
  39. Kawabe H, Mitsuhashi S (1971) Inactivation of dihydrostreptomycin by Staphylococcus aureus. Jpn J Microbiol 15:545–548PubMedGoogle Scholar
  40. Kawabe H, Kondo S, Umezawa H, Mitsuhashi S (1975) R factor-mediated aminoglycoside antibiotic resistance in Pseudomonas aeruginosa: a new aminoglycoside 6’-N-acetyl-transferase. Antimicrob Agents Chemother 7:494–499PubMedGoogle Scholar
  41. Kawabe H, Naganawa H, Kondo S, Umezawa H, Mitsuhashi S (1978) New plasmid-mediated phosphorylation of gentamicin C in Staphylococcus aureus. Microbiol Immunol 22:515–521PubMedGoogle Scholar
  42. Kawabe H, Sakurai H, Fukasawa K, Shimizu S, Hasuda K, Iyobe S, Mitsuhashi S (1979) Phosphorylation and inactivation of streptomycin by plant pathogenic Pseudomonas lachrymans. J Antibiot (Tokyo) 32:425–426Google Scholar
  43. Kawaguchi H, Naito T, Nakagawa S, Fujisawa K (1972) BB-K8, a new semisynthetic aminoglycoside antibiotic. J Antibiot (Tokyo) 25:695–708Google Scholar
  44. Kida M, Igarashi S, Okutani T, Asako T, Hiraga K, Mitsuhashi S (1974) Selective phosphorylation of the 5”-hydroxy group of ribostamycin by a new enzyme from Pseudomonas aeruginosa. Antimicrob Agents Chemother 5:92–94PubMedGoogle Scholar
  45. Kida M, Asako T, Yoneda M, Mitsuhashi S (1975) Phosphorylation of dihydrostreptomycin by Pseudomonas aeruginosa. In: Mitsuhashi S (ed) Microbial drug resistance. University of Tokyo Press, Tokyo, pp 441–448Google Scholar
  46. Kobayashi F, Yamaguchi M, Eda J, Higashi F, Mitsuhashi S (1971) Enzymatic inactivation of gentamicin C components by cell-free extract from Klebsiella pneumoniae. J Antibiot (Tokyo) 24:719–721Google Scholar
  47. Kobayashi F, Yamaguchi M, Sato J, Mitsuhashi S (1972) Purification and properties of di-hydrostreptomycin-phosphorylating enzyme from Pseudomonas aeruginosa. Jpn J Microbiol 16:15–19PubMedGoogle Scholar
  48. Kobayashi F, Koshi T, Eda J, Yoshimura Y, Mitsuhashi S, (1973) Lividomycin resistance in staphylococci by enzymatic phosphorylation. Antimicrob Agents Chemother 4:1–5PubMedGoogle Scholar
  49. Kojima M, Ezaki N, Amano S, Inouye S, Niida T (1975) Bioconversion of ribostamycin (SF-733). II. Isolation and structure of 3-N-acetylribostamycin, a microbiologically inactive product of ribostamycin produced by Streptomyces ribosidificus. J Antibiot (Tokyo) 28:42–47Google Scholar
  50. Kondo S (1979) Some chemical modifications of aminoglycoside antibiotics. Jpn J Antibiot 32:S228–S236PubMedGoogle Scholar
  51. Kondo S, Okanishi M, Utahara R, Maeda K, Umezawa H (1968) Isolation of kanamycin and paromamine inactivated by E. coli carrying R factor. J Antibiot (Tokyo) 21:22–29Google Scholar
  52. Kondo S, Yamamoto H, Naganawa H, Umezawa H, Mitsuhashi S (1972) Isolation and characterization of lividomycin A inactivated by Pseudomonas aeruginosa and Escherichia coli carrying R factor. J Antibiot (Tokyo) 25:483–484Google Scholar
  53. Kondo S, Iinuma K, Yamamoto H, Maeda K, Umezawa H (1973a) Synthesis of 1-N-[(S)-4-amino-2-hydroxybutyryl]-kanamycin B and 3’,4’-dideoxykanamycin B active against kanamycin-resistant bacteria. J Antibiot (Tokyo) 26:412–415Google Scholar
  54. Kondo S, Iinuma K, Yamamoto H, Ikeda Y, Maeda K, Umezawa H (1973b) Syntheses of (5)-4-amino-2-hydroxybutyryl derivatives of 3’,4’-dideoxykanamycin B and their antibacterial activities. J Antibiot (Tokyo) 26:705–707Google Scholar
  55. Kondo S, Iinuma K, Hamada M, Maeda K, Umezawa H (1974) Syntheses of isoseryl derivatives of kanamycins and their antibacterial activities. J Antibiot (Tokyo) 27:90–93Google Scholar
  56. Kondo S, Yamamoto H, Iinuma K, Maeda K, Umezawa H (1976) Syntheses of 6’,5”,6”‘-triamino-6’,5”,6”‘-trideoxylividomycin A and 6’5”-diamino-6’,5”-dideoxylividomycin B. J Antibiot (Tokyo) 29:1134–1136Google Scholar
  57. Kondo S, Miyasaka T, Yoshida K, Iinuma K, Umezawa H (1977) Syntheses and properties of kanamycin C derivatives active against resistant bacteria. J Antibiot (Tokyo) 30:1150–1152Google Scholar
  58. Koyama G, Iitaka Y, Maeda K, Umezawa H (1968) The crystal structure of kanamycin. Tetrahedron Lett 1875–1879Google Scholar
  59. Kumar V, Jones GS, Blacksberg I, Remers WA, Misiek M, Pursiano TA (1980) Aminoglycoside antibiotics. 3.Epimino derivatives of neamine, ribostamycin, and kanamycin B. J Med Chem 23:42–49PubMedGoogle Scholar
  60. LeGoffic F (1977) The resistance of S. aureus to aminoglycoside antibiotics and pristinamy-cins in France in 1976–1977. Jpn J Antibiot 30:S286-S291Google Scholar
  61. LeGoffic F, Chevereau M (1972) L’adenyl-gentamycine C1: un derive de la gentamycine inactivée par des bacteries proteuses d’un R-facteur. C R H S Acad Sci, Ser C 274:535–536Google Scholar
  62. LeGoffic F, Martel A (1974) La résistance aux aminosides provoquée par une isoenzyme la kanamycine acétyltransférase. Biochimie 56:893–987Google Scholar
  63. LeGoffic F, Moreau N (1973) Purification by affinity chromatography of an enzyme involved in gentamicin inactivation. FEBS Lett 29:289–291Google Scholar
  64. LeGoffic F, Martel A, Witchitz J (1974) 3-N Enzymatic acetylation of gentamicin, tobramycin and kanamycin by Escherichia coli carrying an R factor. Antimicrob Agents Chemother 6:680–684Google Scholar
  65. LeGoffic F, Martel A, Capmau ML, Baca B, Goebel P, Chardon H, Soussy CJ, Duval J, Bouanchaud DH (1976) New plasmid-mediated nucleotidylation of aminoglycoside antibiotics in Staphylococcus aureus. Antimicrob Agents Chemother 10:258–264Google Scholar
  66. LeGoffic F, Martel A, Moreau N, Capmau ML, Soussy CJ, Duval J (1977) 2”-O-Phosphorylation of gentamicin components by a Staphylococcus aureus strain carrying a plasmid. Antimicrob Agents Chemother 12:26–30Google Scholar
  67. Maeda K, Kondo S, Okanishi M, Utahara R, Umezawa H (1968) Isolation of paromamine inactivated by Pseudomonas aeruginosa. J Antibiot (Tokyo) 21:458–459Google Scholar
  68. Mallams AK, Vernay HF, Crowe DF, Detre G, Tanabe M, Yasuda DM (1973) The synthesis of 4”-deoxygentamicin C1. J Antibiot (Tokyo) 26:782–783Google Scholar
  69. Matsuhashi Y, Yagisawa M, Kondo S, Takeuchi T, Umezawa H (1975) Aminoglycoside 3’-phosphotransferases I and II in Pseudomonas aeruginosa. J Antibiot (Tokyo) 28:442–447Google Scholar
  70. Matsuhashi Y, Sawa T, Takeuchi T, Umezawa H (1976 a) Purification of aminoglycoside 3’-phosphotransferase II. J Antibiot (Tokyo) 29:204–207Google Scholar
  71. Matsuhashi Y, Sawa T, Takeuchi T, Umezawa H (1976b) Immunological studies of aminoglycoside 3’-phosphotransferases. J Antibiot (Tokyo) 29:1127–1128Google Scholar
  72. Matsuhashi Y, Sawa T, Takeuchi T, Umezawa H, Nagatsu I (1976c) Localization of aminoglycoside 3’-phosphotransferase II on a cellular surface of R factor resistant Escherichia coli. J Antibiot (Tokyo) 29:1129–1130Google Scholar
  73. Matsuhashi Y, Sawa T, Kondo S, Takeuchi T (1977) Aminoglycoside 3’-phosphotransferase in Bacillus circulons producing butirosins. J Antibiot (Tokyo) 30:435–437Google Scholar
  74. Mitsuhashi S (1975) Proposal for a rational nomenclature for phenotype, genotype, and aminoglycoside-aminocyclitol modifying enzyme. In: Mitsuhashi S (ed) Drug action and drug resistance in bacteria. 2. Aminoglycoside antibiotics. University of Tokyo Press, Tokyo, pp 269–275Google Scholar
  75. Mitsuhashi S, Kobayashi F, Yamaguchi M (1971) Enzymatic inactivation of gentamicin C components by cell free extract from Pseudomonas aeruginosa. J Antibiot (Tokyo) 24:400–401Google Scholar
  76. Miyamura S (1961) Dysentery bacilli and its relation to the resistance (in Japanese). Nippon Saikingaku Zasshi 16:115–119PubMedGoogle Scholar
  77. Miyasaka T, Ikeda D, Kondo S, Umezawa H (1980) Syntheses and properties of the 6”-deoxy or 4”,6”-dideoxy derivatives of the kanamycin antibiotics. J Antibiot (Tokyo) 33:527–532Google Scholar
  78. Murase M, Ito T, Fukatsu S, Umezawa H (1970) Studies on kanamycin related compounds produced during fermentation by mutants of Streptomyces kanamyceticus. Isolation and properties. Progr Antimicrob Anticancer Chemother 2:1098–1110Google Scholar
  79. Murray BE, Moellering RC Jr (1979) Aminoglycoside-modifying enzymes among clinical isolates of Acinetobacter calcoaceticus subsp.anitratus (Herellea vaginicola): explanation for high-level aminoglycoside resistance. Antimicrob Agents Chemother 15:190–199PubMedGoogle Scholar
  80. Nagabhushan TL, Wright J J, Cooper AB, Turner WN, Miller GH (1978a) Chemical modification of some gentamicins and sisomicin at the 3”-position. J Antibiot (Tokyo) 31:43–54Google Scholar
  81. Nagabhushan TL, Cooper AB, Tsai H, Daniels PJL, Miller GH (1978b) The syntheses and biological properties of l-N-(S-4-amino-2-hydroxybutyryl)-gentamicin B and 1-N-(S-3-amino-2-hydroxypropionyl)-gentamicin B. J Antibiot (Tokyo) 31:681–687Google Scholar
  82. Naganawa H, Kondo S, Maeda K, Umezawa H (1971a) Structure determination of enzymatically phosphorylated products of aminoglycosidic antibiotics by proton magnetic resonance. J Antibiot (Tokyo) 24:823–829Google Scholar
  83. Naganawa H, Yagisawa M, Kondo S, Takeuchi T, Umezawa H (1971b) The structure determination of an enzymatic inactivation product of 3’4’-dideoxykanamycin B. J Antibiot (Tokyo) 24:913–914Google Scholar
  84. Naito T, Nakagawa S, Abe Y, Fujisawa K, Kawaguchi H (1974) Aminoglycoside antibiotics. VIII. Synthesis and activity of 4’-deoxykanamycin A. J Antibiot (Tokyo) 27:838–850Google Scholar
  85. Naito T, Nakagawa S, Toda S, Fujisawa K, Kawaguchi H (1979) Aminoglycoside antibiotics. XIII. Synthesis and activity of 4’-deoxy-6’-N-methylamikacin and related compounds. J Antibiot (Tokyo) 32:659–664Google Scholar
  86. Nara T, Yamamoto M, Kawamoto I, Takayama K, Okachi R, Takasawa S, Sato T, Sato S (1977) Fortimicins A and B, new aminoglycoside antibiotics. I. Producing organism, fermentation and biological properties of fortimicins. J Antibiot (Tokyo) 30:533–540Google Scholar
  87. Neidle S, Rogers D, Hursthouse MB (1968) The crystal and molecular structure of streptomycin oxime selenate. Tetrahedron Lett 4725–4728Google Scholar
  88. Ochiai K, Yamanaka T, Kimura K, Sawada O (1959) Transfer of resistance from resistant dysentery bacteria to E. coli and vice versa in their mixed culture (in Japanese). Nippon Iji Shimpo 1861:34–37Google Scholar
  89. O’Connor S, Lam LKT, Jones ND, Chaney MO (1976) Apramycin, a unique aminocyclitol antibiotic. J Org Chem 41:2087–2092PubMedGoogle Scholar
  90. Okami Y, Hotta K, Yoshida M, Ikeda D, Kondo S, Umezawa H (1979) New aminoglycoside antibiotics, istamycins A and B. J Antibiot (Tokyo) 32:964–966Google Scholar
  91. Okamoto S, Suzuki Y (1965) Chloramphenicol-, dihydrostreptomycin-and kanamycin-in-activating enzymes from multiple drug-resistant Escherichia coli carrying episome “R”. Nature 108:1301–1303Google Scholar
  92. Okanishi M, Kondo S, Suzuki Y, Okamoto S, Umezawa H (1967) Studies on inactivation of kanamycin and resistances of E. coli. J Antibiot (Tokyo) A20:132–135Google Scholar
  93. Okanishi M, Kondo S, Utahara R, Umezawa H (1968) Phosphorylation and inactivation of aminoglycosidic antibiotics by E. coli carrying R factor. J Antibiot (Tokyo) 21:13–21Google Scholar
  94. Ozanne B, Benveniste R, Tipper D, Davies J (1969) Aminoglycoside antibiotics: inactivation by phosphorylation in Escherichia coli carrying R factors. J Bacteriol 100:1144–1146PubMedGoogle Scholar
  95. Richardson K, Jevons S, Moore JW, Ross BC, Wright JR (1977) Synthesis and antibacterial activities of l-N-[(5)-co-amino-2-hydroxyalkyl]kanamycin A derivatives. J Antibiot (Tokyo) 30:843–846Google Scholar
  96. Richardson K, Brammer KW, Jevons S, Plews RM, Wright JR (1979) Synthesis and antibacterial activity of l-N-(l,3-dihydroxy-2-propyl)kanamycin B (UK-31,214). J Antibiot (Tokyo) 32:973–977Google Scholar
  97. Rinehart KL Jr (1964) The neomycins and related antibiotics. John Wiley, New York London SidneyGoogle Scholar
  98. Rossi D, Goss WA, Daum SJ (1977) Mutational biosynthesis by idiotrophs of Micromono-spora purpurea. I. Conversion of aminocyclitols to new aminoglycoside antibiotics. J Antibiot (Tokyo) 30:88–97Google Scholar
  99. Sano H, Tsuchiya T, Kobayashi S, Hamada M, Umezawa S, Umezawa H (1976) Synthesis of 3”-deoxydihydrostreptomycin active against resistant bacteria. J Antibiot (Tokyo) 29:978–980Google Scholar
  100. Santanam P, Kayser FH (1976) Tobramycin adenylyltransferase: A new aminoglycoside-inactivating enzyme from Staphylococcus epidermidis. J Infect Dis 134:S33-S39PubMedGoogle Scholar
  101. Sato S, Iida T, Okachi R, Shirahata K, Nara T (1977) Enzymatic acetylation of fortimicin A and seldomycin factor 5 by aminoglycoside 3-acetyltransferase I [AAC(3)-I] of E. coli KY8348. J Antibiot (Tokyo) 30:1025–1027Google Scholar
  102. Satoh A, Ogawa H, Satomura Y (1975) Effect of sclerin on production of the aminoglycoside antibiotics accompanied by salvage function in Streptomyces. Agric Biol Chem 39:1593–1598Google Scholar
  103. Smith DH, Janjigian J A, Prescott N, Anderson PW (1970) Resistance factor-mediated spec-tinomycin resistance. Infect Immun 1:120–127PubMedGoogle Scholar
  104. Suami T, Nishiyama S, Ishikawa Y, Umemura E (1978) Modification of aminocyclitol antibiotics. 6. Preparation of 5-deoxykanamycin B. Bull Chem Soc Jpn 51:2354–2357Google Scholar
  105. Suzuki I, Takahashi N, Shirota S, Kawabe H, Mitsuhashi S (1975) Adenylylation of streptomycin by Staphylococcus aureus: a new streptomycin adenylyltransferase. In: Mitsuhashi S (ed) Microbial drug resistance. University of Tokyo Press, Tokyo, pp 463–471Google Scholar
  106. Takagi Y, Miyake T, Tsuchiya T, Umezawa S, Umezawa H (1973) Synthesis of 3’-deoxy-kanamycin B. J Antibiot (Tokyo) 26:403–406Google Scholar
  107. Takasawa S, Utahara R, Okanishi M, Maeda K, Umezawa H (1968) Studies on adenylyl-streptomycin, a product of streptomycin inactivated by E. coli carrying the R factor. J Antibiot (Tokyo) 21:477–484Google Scholar
  108. Tanabe M, Yasuda DM, Detre G (1977) Aminoglycoside antibiotics: synthesis of nebramine, tobramycin and 4”-epi-tobramycin. Tetrahedron Lett 3607–3610Google Scholar
  109. Testa RT, Wagman GH, Daniels PJL, Weinstein MJ (1974) Mutamicins; biosynthetically created new sisomicin analogues. J Antibiot (Tokyo) 27:917–921Google Scholar
  110. Toda S, Nakagawa S, Naito T, Kawaguchi H (1978) Structure determination of amikacin derivatives modified by enzymes from resistant S. aureus strains. Tetrahedron Lett 3917–3920Google Scholar
  111. Tsuchiya T, Jikihara T, Miyake T, Umezawa S, Hamada M, Umezawa H (1979) 3’-Deoxy-amikacin and 3’,4’-dideoxyamikacin and their antibacterial activities. J Antibiot (Tokyo) 32:1351–1353Google Scholar
  112. Umezawa H (1970) Mechanism of inactivation of aminoglycosidic antibiotics by enzymes of resistant organisms of clinical origin. Progr Antimicrob Anticancer Chemother 2:567–571Google Scholar
  113. Umezawa H (1974) Biochemical mechanism of resistance to aminoglycosidic antibiotics. Adv Carbohydr Chem Biochem 30:183–225PubMedGoogle Scholar
  114. Umezawa H (1975) Biochemical mechanism of resistance to aminoglycosidic antibiotics. In: Mitsuhashi S (ed) Drug action and drug resistance in bacteria. 2. Aminoglycoside antibiotics. University of Tokyo Press, Tokyo, pp 211–248Google Scholar
  115. Umezawa H (1979) Studies on aminoglycoside antibiotics: enzymic mechanism of resistance and genetics. Jpn J Antibiot 32:S1–S14PubMedGoogle Scholar
  116. Umezawa H, Ueda M, Maeda K, Yagishita K, Kondo S, Okami Y, Utahara R, Osato Y, Nitta K, Takeuchi T (1957) Production and isolation of a new antibiotic, kanamycin. J Antibiot (Tokyo) A10.181–188Google Scholar
  117. Umezawa H, Okanishi M, Utahara R, Maeda K, Kondo S (1967a) Isolation and structure of kanamycin inactivated by a cell-free system of kanamycin-resistant E. coli. J Antibiot (Tokyo) A20:136–141Google Scholar
  118. Umezawa H, Okanishi M, Kondo S, Hamana K, Utahara R, Maeda K, Mitsuhashi S (1967b) Phosphorylative inactivation of aminoglycosidic antibiotics by Escherichia coli carrying R factor. Science 157:1559–1561PubMedGoogle Scholar
  119. Umezawa H, Takasawa S, Okanishi M, Utahara R, (1968a) Adenylylstreptomycin, a product of streptomycin inactivated by E. coli carrying R factor. J Antibiot (Tokyo) 21:81–82Google Scholar
  120. Umezawa H, Doi O, Ogura M, Kondo S, Tanaka N (1968b) Phosphorylation and inactivation of kanamycin by Pseudomonas aeruginosa. J Antibiot (Tokyo) 21:154–155Google Scholar
  121. Umezawa H, Umezawa S, Tsuchiya T, Okazaki Y (1971) 3’,4’-Dideoxy kanamycin B active against kanamycin-resistant Escherichia coli and Pseudomonas aeruginosa. J Antibiot (Tokyo) 24:485–487Google Scholar
  122. Umezawa H, Nishimura Y, Tsuchiya T, Umezawa S (1972a) Syntheses of 6’-N-methyl-kanamycin and 3’,4’-dideoxy-6’-N-methylkanamycin B active against resistant strains having 6’-N-acetylating enzymes. J Antibiot (Tokyo) 25:743–745Google Scholar
  123. Umezawa H, Tsuchiya T, Muto R, Umezawa S (1972b) Studies on amino sugars. XXIX.-The synthesis of 3’-0-methylkanamycin. Bull Chem Soc Jpn 45:2842–2847Google Scholar
  124. Umezawa H, Yamamoto H, Yagisawa M, Kondo S, Takeuchi T, Chabbert YA (1973a) Kanamycin phosphotransferase I: mechanism of cross-resistance between kanamycin and lividomycin. J Antibiot (Tokyo) 26:407–411Google Scholar
  125. Umezawa H, Yagisawa M, Matsuhashi Y, Naganawa H, Yamamoto H, Kondo S, Takeuchi T, Chabbert YA (1973b) Gentamicin acetyltransferase in Escherichia coli carrying R factor. J Antibiot (Tokyo) 26:612–614Google Scholar
  126. Umezawa H, Matsuhashi Y, Yagisawa M, Yamamoto H, Kondo S, Takeuchi T (1974) Immobilization of phosphotransferases obtained from resistant bacteria. J Antibiot (Tokyo) 27:358–360Google Scholar
  127. Umezawa H, Iinuma K, Kondo S, Hamada M, Maeda K (1975a) Synthesis of 1-N-acyl derivatives of 3’,4’-dideoxy-6’-N-methylkanamycin B and their antibacterial activities. J Antibiot (Tokyo) 28:340–343Google Scholar
  128. Umezawa H, Iinuma K, Kondo S, Maeda K (1975b) Synthesis and antibacterial activity of 6’-N-alkyl derivatives of l-N-[(S)-4-amino-2-hydroxybutyryl]kanamycin. J Antibiot (Tokyo) 28:483–485Google Scholar
  129. Umezawa H, Ikeda D, Miyasaka T, Kondo S (1979) Syntheses and properties of the 6’-C-alkyl derivatives of 3’,4’-dideoxykanamycin B. J Antibiot (Tokyo) 32:1360–1364Google Scholar
  130. Umezawa S, Tsuchiya T, Muto R, Nishimura Y, Umezawa H (1971a) Synthesis of 3’-deoxykanamycin effective against kanamycin-resistant Escherichia coli and Pseudomonas aeruginosa. J Antibiot (Tokyo) 24:274–275Google Scholar
  131. Umezawa S, Tsuchiya T, Jikihara T, Umezawa H (1971b) Synthesis of 3’,4’-dideoxyneamine active against kanamycin-resistant E. coli and P. aeruginosa. J Antibiot (Tokyo) 24:711–712Google Scholar
  132. Umezawa S, Jikihara T, Tsuchiya T, Umezawa H (1972a) Syntheses of 3’-and 4’-0-methylneamine. J Antibiot (Tokyo) 25:322–324Google Scholar
  133. Umezawa S, Tsuchiya T, Ikeda D, Umezawa H (1972b) Syntheses of 3’,4’-dideoxy and 3’,4’,5”-trideoxyribostamycin active against kanamycin-resistant E. coli and P. aeruginosa. J Antibiot (Tokyo) 25:613–616Google Scholar
  134. Umezawa S, Watanabe I, Tsuchiya T, Umezawa H, Hamada M (1972c) Synthesis of 5”-deoxylividomycin B. J Antibiot (Tokyo) 25:617–618Google Scholar
  135. Umezawa S, Ikeda D, Tsuchiya T, Umezawa H (1973) Synthesis of l-N-((S)4-amino-2-hy-droxybutyryl)-3’,4’-dideoxyneamine. J Antibiot (Tokyo) 26:304–306Google Scholar
  136. Umezawa S, Nishimura Y, Hata Y, Tsuchiya T, Yagisawa M, Umezawa H (1974) Synthesis of 4’-deoxykanamycin and its resistance to kanamycin phosphotransferase II. J Antibiot (Tokyo) 27:722–725Google Scholar
  137. Umezawa Y, Yagisawa M, Sawa T, Takeuchi T, Umezawa H, Matsumoto H, Tazaki T (1975) Aminoglycoside 3’-phosphotransferase III. A new phosphotransferase in resistance mechanism. J Antibiot (Tokyo) 28:845–853Google Scholar
  138. Usui T, Tsuchiya T, Umezawa S (1978) 1-and 3-Deamidino derivatives of dihydrostreptomycin and some 1-N-acyl derivatives. J Antibiot (Tokyo) 31:991–996Google Scholar
  139. Vastola AP, Altschaefl J, Harford S (1980) 5-epi-Sisomicin and 5-epi-gentamicin B: substrates for aminoglycoside-modifying enzymes that retain activity against aminogly-coside-resistant bacteria. Antimicrob Agents Chemother 17:798–802PubMedGoogle Scholar
  140. Waitz J A, Miller GH, Moss E Jr, Chiu PJS (1978) Chemotherapeutic evaluation of 5-episi-somicin (Sch 22591), a new semisynthetic aminoglycoside. Antimicrob Agents Chemother 13:41–48PubMedGoogle Scholar
  141. Walker JB, Skorvaga M (1973) Phosphorylation of streptomycin and dihydrostreptomycin by Streptomyces. Enzymatic synthesis of different diphosphorylated derivatives. J Biol Chem 248:2435–2440PubMedGoogle Scholar
  142. Watanabe I, Tsuchiya T, Umezawa S, Umezawa H (1973a) Synthesis of l-N-((S)-4-amino-2-hydroxybutyryl)lividomycin A. J Antibiot (Tokyo) 26:310–312Google Scholar
  143. Watanabe I, Tsuchiya T, Umezawa S, Umezawa H (1973b) Syntheses of 6’-amino-6’-deoxy-lividomycin B and 6’-deoxy-6’-methylamino-and 6’-deoxy-6’-P-hydroxyethylamino)-lividomycin B. J Antibiot (Tokyo) 26:802–804Google Scholar
  144. Watanabe I, Tsuchiya T, Nakamura F, Hamada M, Umezawa S (1978) Synthesis of 5”-amino-3’,5”-dideoxybutirosin A. J Antibiot (Tokyo) 31:863–867Google Scholar
  145. Watanabe I, Deushi T, Yamaguchi T, Kamiya K, Nakayama M, Mori T (1979) The structural elucidation of aminoglycoside antibiotics, sannamycins A and B. J Antibiot (Tokyo) 32:1066–1068Google Scholar
  146. Williams JW, Northrop DB (1976) Purification and properties of gentamicin acetyltrans-ferase I. Biochemistry 15:125–131PubMedGoogle Scholar
  147. Williams JW, Northrop DB (1978a) Kinetic mechanisms of gentamicin acetyltransferase I. Antibiotic-dependent shift from rapid to nonrapid equilibrium random mechanisms. J Biol Chem 253:5902–5907PubMedGoogle Scholar
  148. Williams JW, Northrop DB (1978b) Substrate specificity and structure-activity relationships of gentamicin acetyltransferase. I. Dependence of antibiotic resistance upon substrate Vmax/Km values. J Biol Chem 253:5908–5914PubMedGoogle Scholar
  149. Witchitz JL (1972) Plasmid-mediated gentamicin resistance not associated with kanamycin resistance in Enterobacteriaceae. J Antibiot (Tokyo) 25:622–624Google Scholar
  150. Woo PWK (1975) 5”-Amino-3’,4’,5”-trideoxybutirosin A, a new semi-synthetic aminoglycoside antibiotic. J Antibiot (Tokyo) 28:522–529Google Scholar
  151. Wright JJ (1976) Synthesis of 1-N-ethylsisomicin: a broad-spectrum semisynthetic aminoglycoside antibiotic. J Chem Soc Chem Commun 206–208Google Scholar
  152. Wright JJ, Cooper A, Daniels PJL, Nagabhushan TL, Rane D, Turner WN, Weinstein J (1976) Selective N-acylation of gentamicin antibiotics. Synthesis of 1-N-acyl derivatives. J Antibiot (Tokyo) 29:714–719Google Scholar
  153. Yagisawa M, Naganawa H, Kondo S, Hamada M, Takeuchi T, Umezawa H (1971) Adeny-lyldideoxykanamycin B, a product of the inactivation of dideoxykanamycin B by Escherichia coli carrying R factor. J Antibiot (Tokyo) 24:911–912Google Scholar
  154. Yagisawa M, Naganawa H, Kondo S, Takeuchi T, Umezawa H (1972a) Inactivation of 3’,4’-dideoxykanamycin B by an enzyme solution of resistant E. coli and isolation of 3’,4’-dideoxykanamycin B 2”-guanylate and 2”-inosinate. J Antibiot (Tokyo) 25:492–494Google Scholar
  155. Yagisawa M, Naganawa H, Kondo S, Takeuchi T, Umezawa H (1972b) 6’-N-Acetylation of 3’,4’-dideoxykanamycin B by an enzyme in a resistant strain of Pseudomonas aeruginosa. J Antibiot (Tokyo) 25:495–496Google Scholar
  156. Yagisawa M, Yamamoto H, Naganawa H, Kondo S, Takeuchi T, Umezawa H (1972c) A new enzyme in Escherichia coli carrying R factor phosphorylating 3’-hydroxyl of butirosin A, kanamycin, neamine and ribostamycin. J Antibiot (Tokyo) 25:748–750Google Scholar
  157. Yagisawa M, Kondo S, Takeuchi T, Umezawa H (1975) Aminoglycoside 6’-N-acetyltrans-ferase of Pseudomonas aeruginosa: structural requirements of substrate. J Antibiot (Tokyo) 28:486–489Google Scholar
  158. Yamada T, Tipper D, Davies J (1968) Enzymatic inactivation of streptomycin by R factor-resistant Escherichia coli. Nature 219:288–291PubMedGoogle Scholar
  159. Yamaguchi M, Mitsuhashi S, Kobayashi F, Zenda H (1974) A 2’-N-acetylating enzyme of aminoglycosides. J Antibiot (Tokyo) 27:507–515Google Scholar
  160. Yamamoto H, Kondo S, Maeda K, Umezawa H (1972a) Synthesis of lividomycin A 5”-phosphate, an enzymatically inactivated lividomycin A. J Antibiot (Tokyo) 25:485–486Google Scholar
  161. Yamamoto H, Kondo S, Maeda K, Umezawa H (1972b) Synthesis of 5”-deoxylividomy-cin A and its amino derivatives. J Antibiot (Tokyo) 25:487–488Google Scholar
  162. Yamamoto H, Yagisawa M, Naganawa H, Kondo S, Takeuchi T, Umezawa H (1972c) Kanamycin 6’-acetate and ribostamycin 6’-acetate, enzymatically inactivated products by Pseudomonas aeruginosa. J Antibiot (Tokyo) 25:746–747Google Scholar
  163. Yano H, Fujii H, Mukoo H, Shimura M, Watanabe T, Sekizawa Y (1978) On the enzymatic inactivation of dihydrostreptomycin by Pseudomonas lachrymans, cucumber angular leaf spot bacterium: isolation and structural resolution of the inactivated product. Ann Phytopathol Soc Jpn 44:413–419Google Scholar

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© Springer-Verlag Berlin Heidelberg 1982

Authors and Affiliations

  • H. Umezawa
  • S. Kondo

There are no affiliations available

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