Skip to main content

Mechanisms of Resistance to Aminoglycoside Antibiotics

  • Chapter
Aminoglycoside Antibiotics

Part of the book series: Handbook of Experimental Pharmacology ((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.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abe Y, Nakagawa S, Fujisawa K, Naito T, Kawaguchi H (1977) Aminoglycoside antibiotics. XI. Synthesis and activity of 4’-deoxykanamycin B. J Antibiot (Tokyo) 30:1004–1007

    CAS  Google Scholar 

  • 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 1866:46–50

    Google Scholar 

  • Benveniste R, Davies J (1971a) R-factor mediated gentamicin resistance: a new enzyme which modifies aminoglycoside antibiotics. FEBS Lett 14:293–296

    PubMed  CAS  Google Scholar 

  • Benveniste R, Davies J (1971b) Enzymatic acetylation of aminoglycoside antibiotics by Escherichia coli carrying an R-factor. Biochemistry 10:1787–1796

    PubMed  CAS  Google Scholar 

  • 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 70:2276–2280

    PubMed  CAS  Google Scholar 

  • Benveniste R, Yamada T, Davies J (1970) Enzymatic adenylylation of streptomycin and spectinomycin by R-factor-resistant Escherichia coli. Infect Immun 1:109–119

    PubMed  CAS  Google Scholar 

  • Brzezinska M, Davies J (1973) Two enzymes which phosphorylate neomycin and kanamy-cin in Escherichia coli strains carrying R factors. Antimicrob Agents Chemother 3:266–269

    PubMed  CAS  Google Scholar 

  • 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 11:761–765

    PubMed  CAS  Google Scholar 

  • 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 13:598–603

    PubMed  CAS  Google Scholar 

  • Cochran TG, Abraham DJ (1972) Stereochemistry and absolute configuration of the antibiotic spectinomycin: an X-ray diffraction study. J Chem Soc Chem Commun 494–495

    Google Scholar 

  • 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 74:999–1008

    PubMed  CAS  Google Scholar 

  • Culbertson TP, Watson DR, Haskell TH (1973) 5”-Amino-5”-deoxybutirosin, a new semisynthetic aminoglycoside antibiotic. J Antibiot (Tokyo) 26:790–793

    CAS  Google Scholar 

  • 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) 27:150–154

    CAS  Google Scholar 

  • 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) 27:889–893

    CAS  Google Scholar 

  • 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-S204

    PubMed  CAS  Google Scholar 

  • 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 14:69–72

    PubMed  CAS  Google Scholar 

  • Davies J, Smith DI (1978) Plasmid-determined resistance to antimicrobial agents. Ann Rev Microbiol 32:469–518

    CAS  Google Scholar 

  • 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) 32:173–179

    CAS  Google Scholar 

  • 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) 32:187–192

    CAS  Google Scholar 

  • Deushi T, Iwasaki A, Kamiya K, Mizoguchi T, Nakayama M, Itoh H, Mori T (1979c) New aminoglycoside antibiotics, sannamycin. J Antibiot (Tokyo) 32:1061–1065

    CAS  Google Scholar 

  • 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 16:1276–1281

    PubMed  CAS  Google Scholar 

  • Doi O, Miyamoto M, Tanaka N, Umezawa H (1968b) Inactivation and phosphorylation of kanamycin by drug-resistant Staphylococcus aureus. Appl Microbiol 16:1282–1284

    PubMed  CAS  Google Scholar 

  • Doi O, Kondo S, Tanaka N, Umezawa H (1969) Purification and properties of kanamycin-phosphorylating enzyme from Pseudomonas aeruginosa. J Antibiot (Tokyo) 22:273–282

    CAS  Google Scholar 

  • 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) 30:552–563

    CAS  Google Scholar 

  • Fu KP, Neu HC (1978) Activity of 5-episisomicin compared with that of other aminoglycosides. Antimicrob Agents Chemother 14:194–200

    PubMed  CAS  Google Scholar 

  • 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) 33:122–123

    CAS  Google Scholar 

  • 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 9:945–950

    PubMed  CAS  Google Scholar 

  • Hanessian S, Yatele J (1980) Aminoglycoside antibiotics. 4’-Deoxyneomycin and 4’-deoxy-paromamine. J Antibiot (Tokyo) 33:675–678

    CAS  Google Scholar 

  • Hanessian S, Massé R, Capmeau M (1977) Aminoglycoside antibiotics: synthesis of 5”-amino-5”-deoxyneomycin and 5”-amino-5”-deoxyparomomycin. J Antibiot (Tokyo) 30:893–896

    CAS  Google Scholar 

  • Hirayama N, Shirahata K, Ohashi Y, Sasada Y, Martin JR (1978) Structure of fortimicin B. Acta Crystallogr Sect B Struct Crystallogr Cryst Chem B34:2648–2650

    CAS  Google Scholar 

  • Hsiang MW, White TJ, Davies JE (1978) NH2-Terminal sequence of the aminoglycoside acetyltransferase (3)-I mediated by plasmid RIP 135. FEBS Lett 92:97–99

    PubMed  CAS  Google Scholar 

  • Hori M, Umezawa H (1967) Miscoding activities of biologically inactivated kanamycins. J Antiobiot (Tokyo) A20:386–387

    Google Scholar 

  • Iida T, Sato M, Matsubara I, Mori Y, Shirahata K (1979) The structures of fortimicins C, D, and KE. J Antibiot (Tokyo) 32:1273–1279

    CAS  Google Scholar 

  • Ikeda D, Tsuchiya T, Umezawa S, Umezawa H, Hamada M (1973a) Synthesis of 3’,4’-dideoxybutirosin B. J Antibiot (Tokyo) 26:307–309

    CAS  Google Scholar 

  • Ikeda D, Tsuchiya T, Umezawa S, Umezawa H (1973b) Synthesis of 3’-deoxyribostamycin. J Antibiot (Tokyo) 26:799–801

    CAS  Google Scholar 

  • Ikeda D, Nagaki F, Umezawa S, Tsuchiya T, Umezawa H (1975) Synthesis of 3’-deoxy-butirosin B. J Antibiot (Tokyo) 28:616–618

    CAS  Google Scholar 

  • 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) 32:1357–1359

    CAS  Google Scholar 

  • 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) 32:1354–1356

    CAS  Google Scholar 

  • Kawabe H, Mitsuhashi S (1971) Inactivation of dihydrostreptomycin by Staphylococcus aureus. Jpn J Microbiol 15:545–548

    PubMed  CAS  Google Scholar 

  • 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 7:494–499

    PubMed  CAS  Google Scholar 

  • Kawabe H, Naganawa H, Kondo S, Umezawa H, Mitsuhashi S (1978) New plasmid-mediated phosphorylation of gentamicin C in Staphylococcus aureus. Microbiol Immunol 22:515–521

    PubMed  CAS  Google Scholar 

  • 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) 32:425–426

    CAS  Google Scholar 

  • Kawaguchi H, Naito T, Nakagawa S, Fujisawa K (1972) BB-K8, a new semisynthetic aminoglycoside antibiotic. J Antibiot (Tokyo) 25:695–708

    CAS  Google Scholar 

  • 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 5:92–94

    PubMed  CAS  Google Scholar 

  • 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 441–448

    Google Scholar 

  • 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) 24:719–721

    CAS  Google Scholar 

  • Kobayashi F, Yamaguchi M, Sato J, Mitsuhashi S (1972) Purification and properties of di-hydrostreptomycin-phosphorylating enzyme from Pseudomonas aeruginosa. Jpn J Microbiol 16:15–19

    PubMed  CAS  Google Scholar 

  • Kobayashi F, Koshi T, Eda J, Yoshimura Y, Mitsuhashi S, (1973) Lividomycin resistance in staphylococci by enzymatic phosphorylation. Antimicrob Agents Chemother 4:1–5

    PubMed  CAS  Google Scholar 

  • 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) 28:42–47

    CAS  Google Scholar 

  • Kondo S (1979) Some chemical modifications of aminoglycoside antibiotics. Jpn J Antibiot 32:S228–S236

    PubMed  CAS  Google Scholar 

  • 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) 21:22–29

    CAS  Google Scholar 

  • 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) 25:483–484

    CAS  Google Scholar 

  • 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) 26:412–415

    CAS  Google Scholar 

  • 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) 26:705–707

    CAS  Google Scholar 

  • Kondo S, Iinuma K, Hamada M, Maeda K, Umezawa H (1974) Syntheses of isoseryl derivatives of kanamycins and their antibacterial activities. J Antibiot (Tokyo) 27:90–93

    CAS  Google Scholar 

  • 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) 29:1134–1136

    CAS  Google Scholar 

  • 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) 30:1150–1152

    CAS  Google Scholar 

  • Koyama G, Iitaka Y, Maeda K, Umezawa H (1968) The crystal structure of kanamycin. Tetrahedron Lett 1875–1879

    Google Scholar 

  • 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 23:42–49

    PubMed  CAS  Google Scholar 

  • LeGoffic F (1977) The resistance of S. aureus to aminoglycoside antibiotics and pristinamy-cins in France in 1976–1977. Jpn J Antibiot 30:S286-S291

    Google Scholar 

  • 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 274:535–536

    CAS  Google Scholar 

  • LeGoffic F, Martel A (1974) La résistance aux aminosides provoquée par une isoenzyme la kanamycine acétyltransférase. Biochimie 56:893–987

    CAS  Google Scholar 

  • LeGoffic F, Moreau N (1973) Purification by affinity chromatography of an enzyme involved in gentamicin inactivation. FEBS Lett 29:289–291

    CAS  Google Scholar 

  • 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 6:680–684

    CAS  Google Scholar 

  • 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 10:258–264

    CAS  Google Scholar 

  • 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 12:26–30

    CAS  Google Scholar 

  • Maeda K, Kondo S, Okanishi M, Utahara R, Umezawa H (1968) Isolation of paromamine inactivated by Pseudomonas aeruginosa. J Antibiot (Tokyo) 21:458–459

    CAS  Google Scholar 

  • Mallams AK, Vernay HF, Crowe DF, Detre G, Tanabe M, Yasuda DM (1973) The synthesis of 4”-deoxygentamicin C1. J Antibiot (Tokyo) 26:782–783

    CAS  Google Scholar 

  • Matsuhashi Y, Yagisawa M, Kondo S, Takeuchi T, Umezawa H (1975) Aminoglycoside 3’-phosphotransferases I and II in Pseudomonas aeruginosa. J Antibiot (Tokyo) 28:442–447

    CAS  Google Scholar 

  • Matsuhashi Y, Sawa T, Takeuchi T, Umezawa H (1976 a) Purification of aminoglycoside 3’-phosphotransferase II. J Antibiot (Tokyo) 29:204–207

    CAS  Google Scholar 

  • Matsuhashi Y, Sawa T, Takeuchi T, Umezawa H (1976b) Immunological studies of aminoglycoside 3’-phosphotransferases. J Antibiot (Tokyo) 29:1127–1128

    CAS  Google Scholar 

  • 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) 29:1129–1130

    CAS  Google Scholar 

  • Matsuhashi Y, Sawa T, Kondo S, Takeuchi T (1977) Aminoglycoside 3’-phosphotransferase in Bacillus circulons producing butirosins. J Antibiot (Tokyo) 30:435–437

    CAS  Google Scholar 

  • 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 269–275

    Google Scholar 

  • Mitsuhashi S, Kobayashi F, Yamaguchi M (1971) Enzymatic inactivation of gentamicin C components by cell free extract from Pseudomonas aeruginosa. J Antibiot (Tokyo) 24:400–401

    CAS  Google Scholar 

  • Miyamura S (1961) Dysentery bacilli and its relation to the resistance (in Japanese). Nippon Saikingaku Zasshi 16:115–119

    PubMed  CAS  Google Scholar 

  • 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) 33:527–532

    CAS  Google Scholar 

  • 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 2:1098–1110

    CAS  Google Scholar 

  • 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 15:190–199

    PubMed  CAS  Google Scholar 

  • 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) 31:43–54

    CAS  Google Scholar 

  • 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) 31:681–687

    CAS  Google Scholar 

  • 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) 24:823–829

    CAS  Google Scholar 

  • 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) 24:913–914

    CAS  Google Scholar 

  • Naito T, Nakagawa S, Abe Y, Fujisawa K, Kawaguchi H (1974) Aminoglycoside antibiotics. VIII. Synthesis and activity of 4’-deoxykanamycin A. J Antibiot (Tokyo) 27:838–850

    CAS  Google Scholar 

  • 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) 32:659–664

    CAS  Google Scholar 

  • 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) 30:533–540

    CAS  Google Scholar 

  • Neidle S, Rogers D, Hursthouse MB (1968) The crystal and molecular structure of streptomycin oxime selenate. Tetrahedron Lett 4725–4728

    Google Scholar 

  • 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 1861:34–37

    Google Scholar 

  • O’Connor S, Lam LKT, Jones ND, Chaney MO (1976) Apramycin, a unique aminocyclitol antibiotic. J Org Chem 41:2087–2092

    PubMed  Google Scholar 

  • Okami Y, Hotta K, Yoshida M, Ikeda D, Kondo S, Umezawa H (1979) New aminoglycoside antibiotics, istamycins A and B. J Antibiot (Tokyo) 32:964–966

    CAS  Google Scholar 

  • Okamoto S, Suzuki Y (1965) Chloramphenicol-, dihydrostreptomycin-and kanamycin-in-activating enzymes from multiple drug-resistant Escherichia coli carrying episome “R”. Nature 108:1301–1303

    Google Scholar 

  • Okanishi M, Kondo S, Suzuki Y, Okamoto S, Umezawa H (1967) Studies on inactivation of kanamycin and resistances of E. coli. J Antibiot (Tokyo) A20:132–135

    Google Scholar 

  • Okanishi M, Kondo S, Utahara R, Umezawa H (1968) Phosphorylation and inactivation of aminoglycosidic antibiotics by E. coli carrying R factor. J Antibiot (Tokyo) 21:13–21

    CAS  Google Scholar 

  • Ozanne B, Benveniste R, Tipper D, Davies J (1969) Aminoglycoside antibiotics: inactivation by phosphorylation in Escherichia coli carrying R factors. J Bacteriol 100:1144–1146

    PubMed  CAS  Google Scholar 

  • 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) 30:843–846

    CAS  Google Scholar 

  • 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) 32:973–977

    CAS  Google Scholar 

  • Rinehart KL Jr (1964) The neomycins and related antibiotics. John Wiley, New York London Sidney

    Google Scholar 

  • 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) 30:88–97

    Google Scholar 

  • Sano H, Tsuchiya T, Kobayashi S, Hamada M, Umezawa S, Umezawa H (1976) Synthesis of 3”-deoxydihydrostreptomycin active against resistant bacteria. J Antibiot (Tokyo) 29:978–980

    CAS  Google Scholar 

  • Santanam P, Kayser FH (1976) Tobramycin adenylyltransferase: A new aminoglycoside-inactivating enzyme from Staphylococcus epidermidis. J Infect Dis 134:S33-S39

    PubMed  Google Scholar 

  • 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) 30:1025–1027

    CAS  Google Scholar 

  • 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 39:1593–1598

    CAS  Google Scholar 

  • Smith DH, Janjigian J A, Prescott N, Anderson PW (1970) Resistance factor-mediated spec-tinomycin resistance. Infect Immun 1:120–127

    PubMed  CAS  Google Scholar 

  • Suami T, Nishiyama S, Ishikawa Y, Umemura E (1978) Modification of aminocyclitol antibiotics. 6. Preparation of 5-deoxykanamycin B. Bull Chem Soc Jpn 51:2354–2357

    CAS  Google Scholar 

  • 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 463–471

    Google Scholar 

  • Takagi Y, Miyake T, Tsuchiya T, Umezawa S, Umezawa H (1973) Synthesis of 3’-deoxy-kanamycin B. J Antibiot (Tokyo) 26:403–406

    CAS  Google Scholar 

  • 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) 21:477–484

    CAS  Google Scholar 

  • Tanabe M, Yasuda DM, Detre G (1977) Aminoglycoside antibiotics: synthesis of nebramine, tobramycin and 4”-epi-tobramycin. Tetrahedron Lett 3607–3610

    Google Scholar 

  • Testa RT, Wagman GH, Daniels PJL, Weinstein MJ (1974) Mutamicins; biosynthetically created new sisomicin analogues. J Antibiot (Tokyo) 27:917–921

    CAS  Google Scholar 

  • Toda S, Nakagawa S, Naito T, Kawaguchi H (1978) Structure determination of amikacin derivatives modified by enzymes from resistant S. aureus strains. Tetrahedron Lett 3917–3920

    Google Scholar 

  • 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) 32:1351–1353

    CAS  Google Scholar 

  • Umezawa H (1970) Mechanism of inactivation of aminoglycosidic antibiotics by enzymes of resistant organisms of clinical origin. Progr Antimicrob Anticancer Chemother 2:567–571

    CAS  Google Scholar 

  • Umezawa H (1974) Biochemical mechanism of resistance to aminoglycosidic antibiotics. Adv Carbohydr Chem Biochem 30:183–225

    PubMed  CAS  Google Scholar 

  • 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 211–248

    Google Scholar 

  • Umezawa H (1979) Studies on aminoglycoside antibiotics: enzymic mechanism of resistance and genetics. Jpn J Antibiot 32:S1–S14

    PubMed  CAS  Google Scholar 

  • 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) A10.181–188

    Google Scholar 

  • 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) A20:136–141

    Google Scholar 

  • 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 157:1559–1561

    PubMed  CAS  Google Scholar 

  • Umezawa H, Takasawa S, Okanishi M, Utahara R, (1968a) Adenylylstreptomycin, a product of streptomycin inactivated by E. coli carrying R factor. J Antibiot (Tokyo) 21:81–82

    CAS  Google Scholar 

  • Umezawa H, Doi O, Ogura M, Kondo S, Tanaka N (1968b) Phosphorylation and inactivation of kanamycin by Pseudomonas aeruginosa. J Antibiot (Tokyo) 21:154–155

    CAS  Google Scholar 

  • 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) 24:485–487

    CAS  Google Scholar 

  • 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) 25:743–745

    CAS  Google Scholar 

  • Umezawa H, Tsuchiya T, Muto R, Umezawa S (1972b) Studies on amino sugars. XXIX.-The synthesis of 3’-0-methylkanamycin. Bull Chem Soc Jpn 45:2842–2847

    CAS  Google Scholar 

  • 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) 26:407–411

    CAS  Google Scholar 

  • 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) 26:612–614

    CAS  Google Scholar 

  • Umezawa H, Matsuhashi Y, Yagisawa M, Yamamoto H, Kondo S, Takeuchi T (1974) Immobilization of phosphotransferases obtained from resistant bacteria. J Antibiot (Tokyo) 27:358–360

    CAS  Google Scholar 

  • 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) 28:340–343

    CAS  Google Scholar 

  • 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) 28:483–485

    CAS  Google Scholar 

  • 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) 32:1360–1364

    CAS  Google Scholar 

  • 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) 24:274–275

    CAS  Google Scholar 

  • 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) 24:711–712

    CAS  Google Scholar 

  • Umezawa S, Jikihara T, Tsuchiya T, Umezawa H (1972a) Syntheses of 3’-and 4’-0-methylneamine. J Antibiot (Tokyo) 25:322–324

    CAS  Google Scholar 

  • 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) 25:613–616

    CAS  Google Scholar 

  • Umezawa S, Watanabe I, Tsuchiya T, Umezawa H, Hamada M (1972c) Synthesis of 5”-deoxylividomycin B. J Antibiot (Tokyo) 25:617–618

    CAS  Google Scholar 

  • 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) 26:304–306

    CAS  Google Scholar 

  • 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) 27:722–725

    CAS  Google Scholar 

  • 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) 28:845–853

    CAS  Google Scholar 

  • Usui T, Tsuchiya T, Umezawa S (1978) 1-and 3-Deamidino derivatives of dihydrostreptomycin and some 1-N-acyl derivatives. J Antibiot (Tokyo) 31:991–996

    Google Scholar 

  • 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 17:798–802

    PubMed  CAS  Google Scholar 

  • 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 13:41–48

    PubMed  CAS  Google Scholar 

  • Walker JB, Skorvaga M (1973) Phosphorylation of streptomycin and dihydrostreptomycin by Streptomyces. Enzymatic synthesis of different diphosphorylated derivatives. J Biol Chem 248:2435–2440

    PubMed  CAS  Google Scholar 

  • Watanabe I, Tsuchiya T, Umezawa S, Umezawa H (1973a) Synthesis of l-N-((S)-4-amino-2-hydroxybutyryl)lividomycin A. J Antibiot (Tokyo) 26:310–312

    CAS  Google Scholar 

  • 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) 26:802–804

    CAS  Google Scholar 

  • Watanabe I, Tsuchiya T, Nakamura F, Hamada M, Umezawa S (1978) Synthesis of 5”-amino-3’,5”-dideoxybutirosin A. J Antibiot (Tokyo) 31:863–867

    CAS  Google Scholar 

  • 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) 32:1066–1068

    CAS  Google Scholar 

  • Williams JW, Northrop DB (1976) Purification and properties of gentamicin acetyltrans-ferase I. Biochemistry 15:125–131

    PubMed  CAS  Google Scholar 

  • Williams JW, Northrop DB (1978a) Kinetic mechanisms of gentamicin acetyltransferase I. Antibiotic-dependent shift from rapid to nonrapid equilibrium random mechanisms. J Biol Chem 253:5902–5907

    PubMed  CAS  Google Scholar 

  • 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 253:5908–5914

    PubMed  CAS  Google Scholar 

  • Witchitz JL (1972) Plasmid-mediated gentamicin resistance not associated with kanamycin resistance in Enterobacteriaceae. J Antibiot (Tokyo) 25:622–624

    CAS  Google Scholar 

  • Woo PWK (1975) 5”-Amino-3’,4’,5”-trideoxybutirosin A, a new semi-synthetic aminoglycoside antibiotic. J Antibiot (Tokyo) 28:522–529

    CAS  Google Scholar 

  • Wright JJ (1976) Synthesis of 1-N-ethylsisomicin: a broad-spectrum semisynthetic aminoglycoside antibiotic. J Chem Soc Chem Commun 206–208

    Google Scholar 

  • 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) 29:714–719

    CAS  Google Scholar 

  • 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) 24:911–912

    CAS  Google Scholar 

  • 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) 25:492–494

    CAS  Google Scholar 

  • 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) 25:495–496

    CAS  Google Scholar 

  • 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) 25:748–750

    CAS  Google Scholar 

  • Yagisawa M, Kondo S, Takeuchi T, Umezawa H (1975) Aminoglycoside 6’-N-acetyltrans-ferase of Pseudomonas aeruginosa: structural requirements of substrate. J Antibiot (Tokyo) 28:486–489

    CAS  Google Scholar 

  • Yamada T, Tipper D, Davies J (1968) Enzymatic inactivation of streptomycin by R factor-resistant Escherichia coli. Nature 219:288–291

    PubMed  CAS  Google Scholar 

  • Yamaguchi M, Mitsuhashi S, Kobayashi F, Zenda H (1974) A 2’-N-acetylating enzyme of aminoglycosides. J Antibiot (Tokyo) 27:507–515

    CAS  Google Scholar 

  • Yamamoto H, Kondo S, Maeda K, Umezawa H (1972a) Synthesis of lividomycin A 5”-phosphate, an enzymatically inactivated lividomycin A. J Antibiot (Tokyo) 25:485–486

    CAS  Google Scholar 

  • Yamamoto H, Kondo S, Maeda K, Umezawa H (1972b) Synthesis of 5”-deoxylividomy-cin A and its amino derivatives. J Antibiot (Tokyo) 25:487–488

    CAS  Google Scholar 

  • 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) 25:746–747

    CAS  Google Scholar 

  • 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 44:413–419

    CAS  Google Scholar 

Download references

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 1982 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Umezawa, H., Kondo, S. (1982). Mechanisms of Resistance to Aminoglycoside Antibiotics. In: Umezawa, H., Hooper, I.R. (eds) Aminoglycoside Antibiotics. Handbook of Experimental Pharmacology, vol 62. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-68579-8_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-68579-8_6

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-68581-1

  • Online ISBN: 978-3-642-68579-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics