Methylation of RNA and Resistance to Antibiotics

  • E. Cundliffe
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 91)


Microorganisms have evolved or acquired various modes of resistance to antibiotics, as discussed in depth in this volume. In some cases, active drug molecules may be physically prevented from encountering the target site(s) at which they normally act, either by direct exclusion at membrane barriers or by chemical inactivation due to extracellular enzymes (e.g. β-lactamases). In other instances, where total exclusion of the drug from the cytoplasm cannot be achieved, resistance may depend upon the operation of antibiotic efflux mechanisms (e.g. for tetracycline) or upon drug inactivation by intracellular enzymes and cofactors (e.g. for aminoglycosides). Thus, in some organisms, a critical balance may be struck between drug accumulation on the one hand and its removal or inactivation on the other, so that inhibitory drug concentrations are not established intracellularly.


Ribosomal Ribonucleic Acid Translational Attenuation Methylase Protein ermC Gene Strain JR14 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Allen NE (1977) Macrolide resistance in Staphylococcus aureus: inducers of macrolide resistance. Antimicrob Agents Chemother 11: 669–674PubMedGoogle Scholar
  2. Beauclerk AAD, Cundliffe E (1987) Sites of action of two ribosomal RNA methylases responsible for resistance to aminoglycosides. J Mol Biol 193: 661–671PubMedCrossRefGoogle Scholar
  3. Beauclerk AAD, Hummel H, Holmes DJ, Böck A, Cundliffe E (1985) Studies of the GTPase domain of archaebacterial ribosomes. Eur J Biochem 151: 245–255PubMedCrossRefGoogle Scholar
  4. Benveniste R, Davies J (1973) Aminoglycoside antibiotic-inactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria. Proc Natl Acad Sci USA 70: 2276–2280PubMedCrossRefGoogle Scholar
  5. Bibb MJ, Bibb MJ, Ward JM, Cohen SN (1985) Nucleotide sequences encoding and promoting expression of three antibiotic resistance genes indigenous to Streptomyces. Mol Gen Genet 199: 26–36PubMedCrossRefGoogle Scholar
  6. Chabbert Y (1956) Antagonisme in vitro entre l’erythromycine et la spiramycine. Ann Inst Pasteur 90: 787–790Google Scholar
  7. Crameri R, Davies JE (1986) Increased production of aminoglycosides associated with amplified antibiotic resistance genes. J Antibiot (Tokyo) 39: 128–135Google Scholar
  8. Cundliffe E (1978) Mechanism of resistance to thiostrepton in the producing-organism, Streptomyces azureus. Nature 272: 792–795PubMedCrossRefGoogle Scholar
  9. Cundliffe E (1979) Thiostrepton and related antibiotics. In: Hahn FE (ed) Antibiotics V/I. Mechanism of action of antibacterial agents. Springer, Berlin Heidelberg New York, pp 329–343Google Scholar
  10. Cundliffe E (1980) Antibiotics and prokaryotic ribosomes: action, interaction and resistance. In: Chambliss G, Craven GR, Davies J, Davis K, Kahan L, Nomura M (eds) Ribosomes: structure, function and genetics. University Park Press, Baltimore, pp 555–581Google Scholar
  11. Cundliffe E (1984) Self defence in antibiotic-producing organisms. Br Med Bull 40: 61–67PubMedGoogle Scholar
  12. Cundliffe E (1986) Involvement of specific portions of ribosomal RNA in defined ribosomal functions: a study utilising antibiotics. In: Hardesty B, Kramer G (eds) Structure, function and genetics of ribosomes. Springer, Berlin Heidelberg New York Tokyo, pp 586–604CrossRefGoogle Scholar
  13. Cundliffe E, Thompson J (1979) Ribose methylation and resistance to thiostrepton. Nature 278: 859–861PubMedCrossRefGoogle Scholar
  14. Davies J (1980) Enzymes modifying aminocyclitol antibiotics and their roles in resistance determination and biosynthesis. In: Rinehart KL Jr, Suami T (eds) Aminocyclitol antibiotics. American Chemical Society, Washington DC, pp 323–334CrossRefGoogle Scholar
  15. Denoya CD, Bechhofer DH, Dubnau D (1986) Translational autoregulation of ermC 23S rRNA methyltransferase expression in Bacillus subtilis. J Bacteriol 168: 1133–1141PubMedGoogle Scholar
  16. Dubnau D (1984) Translational attenuation: the regulation of bacterial resistance to the macrolide-lincosamide-streptogramin B antibiotics. CRC Crit Rev Biochem 16: 103–132PubMedCrossRefGoogle Scholar
  17. Fujisawa Y, Weisblum B (1981) A family of r-determinants in Streptomyces spp that specifies inducible resistance to macrolide, lincosamide, and streptogramin type B antibiotics. J Bacteriol 146: 621–631PubMedGoogle Scholar
  18. Gale EF, Cundliffe E, Reynolds PE, Richmond MH, Waring MJ (1981) The molecular basis of antibiotic action. Wiley, LondonGoogle Scholar
  19. Garrod LP (1957) The erythromycin group of antibiotics. Br Med J 2: 57–63PubMedCrossRefGoogle Scholar
  20. Graham MY, Weisblum B (1979) 23S ribosomal ribonucleic acid of macrolide-producing streptomycetes contains methylated adenine. J Bacteriol 137:1464–1467PubMedGoogle Scholar
  21. Gryczan TJ, Grandi G, Hahn J, Grandi R, Dubnau D (1980) Conformational alteration of mRNA structure and the post-transcriptional regulation of erythromycin-induced drug resistance. Nucleic Acids Res 8: 6081–6097PubMedCrossRefGoogle Scholar
  22. Gryczan T, Israeli-Reches M, Del Bue M, Dubnau D (1984) DNA sequence and regulation of ermD, a macrolide-lincosamide-streptogramin B resistance element from Bacillus licheniformis. Mol Gen Genet 194: 349–356PubMedCrossRefGoogle Scholar
  23. Hahn J, Grandi G, Gryczan TJ, Dubnau D (1982) Translational attenuation of ermC: a deletion analysis. Mol Gen Genet 186: 204–216PubMedCrossRefGoogle Scholar
  24. Highland JH, Howard GA, Ochsner E, Stöffler G, Hasenbank R, Gordon J (1975) Identification of a ribosomal protein necessary for thiostrepton binding to E. coli ribosomes. J Biol Chem 250: 1141–1145PubMedGoogle Scholar
  25. Hopwood DA, Bibb MJ, Chater KF, Janssen GR, Malpartida F, Smith CP (1986) Regulation of gene expression in antibiotic-producing Streptomyces. Symp Soc Gen Microbiol 39: 251–276Google Scholar
  26. Horinouchi S, Weisblum B (1980) Posttranscriptional modification of mRNA conformation: mechanism that regulates erythromycin-induced resistance. Proc Natl Acad Sci USA 77: 7079–7083PubMedCrossRefGoogle Scholar
  27. Horinouchi S, Weisblum B (1981) The control region for erythromycin resistance: free energy changes related to induction and mutation to constitutive expression. Mol Gen Genet 182: 341–348PubMedCrossRefGoogle Scholar
  28. Horinouchi S, Byeon WH, Weisblum B (1983) A complex attenuator regulates inducible resistance to macrolides, lincosamides, and streptogramin type B antibiotics in Streptococcus sanguis. J Bacteriol 154: 1252–1262PubMedGoogle Scholar
  29. Hotta K, Yamamoto H, Okami Y, Umezawa H (1981) Resistance mechanisms of kanamycin-, neomycin-, and streptomycin-producing streptomycetes to aminoglycoside antibiotics. J Antibiot (Tokyo) 34: 1175–1182Google Scholar
  30. Jones WF Jr, Nichols RL, Finland M (1956) Development of resistance and cross resistance in vivo to erythromycin, carbomycin, oleandomycin, and streptogramin. Proc Soc Exp Biol Med 93: 388–393PubMedGoogle Scholar
  31. Kamimiya S, Weisblum B (1987) Inducible macrolide-lincosamide-streptogramin resistance in Streptomyces: cloning and characterization of inducible erm from Streptomyces viridochromogenes and Streptomyces fradiae. In: Alacevie M, Hranueli D, Toman Z (eds) Genetics of industrial microorganisms - 86: part B. Pliva, Zagreb, pp 169–175Google Scholar
  32. Kono M, Hashimoto H, Matsuhashi S (1966) Drug resistance of staphylococci. III. Resistance to some macrolide antibiotics and inducible system. Jpn J Microbiol 10: 59–66PubMedGoogle Scholar
  33. Lai CJ (1972) Erythromycin-inducible resistance in Staphylococcus aureus. PhD thesis, University of WisconsinGoogle Scholar
  34. Lai CJ, Weisblum B (1971) Altered methylation of ribosomal RNA in an erythromycin-resistant strain of Staphylococcus aureus. Proc Natl Acad Sci USA 68: 856–860PubMedCrossRefGoogle Scholar
  35. Lai CJ, Dahlberg JE, Weisblum B (1973a) Structure of an inducibly methylatable nucleotide sequence in 23S ribosomal ribonucleic acid from erythromycin-resistant Staphylococcus aureus. Biochemistry 12: 457–460PubMedCrossRefGoogle Scholar
  36. Lai CJ, Weisblum B, Fahnestock SR, Nomura M (1973b) Alteration of 23S ribosomal ribonucleic acid and erythromycin-induced resistance to lincomycin and spiramycin in Staphylococcus aureus. J Mol Biol 74: 67–72PubMedCrossRefGoogle Scholar
  37. Matkovie B, Piendl W, Böck A (1984) Ribosomal resistance as a widespread self-defence mechanism in aminoglycoside-producing Micromonospora species. FEMS Microbiol Lett 24: 273–276CrossRefGoogle Scholar
  38. Matsuhashi Y, Murakami T, Nojiri C, Toyama H, Anzai H, Nagaoka K (1985) Mechanisms of aminoglycoside-resistance of Streptomyces harbouring resistant genes obtained from antibiotic-producers. J Antibiot (Tokyo) 38: 279–282Google Scholar
  39. Murakami T, Nojiri C, Toyama H, Hayashi E, Katumata K, Anzai H, Matsuhashi Y, Yamada Y, Nagaoka K (1983) Cloning of antibiotic-resistance genes in Streptomyces. J Antibiot (Tokyo) 36: 1305–1311Google Scholar
  40. Murphy E (1985) Nucleotide sequence of ermA, a macrolide-lincosamide-streptogramin B determinant in Staphylococcus aureus. J Bacteriol 162: 633–640PubMedGoogle Scholar
  41. Nakajima Y, Inoue M, Oka Y, Yamagishi S (1968) A mode of resistance to macrolide antibiotics in Staphylococcus aureus. Jpn J Microbiol 12: 248–250PubMedGoogle Scholar
  42. Nakano MM, Ogawara H (1987) Isolation and characterization of ribosome resistance gene from Streptomyces kanamyceticus. In: Alacevié M, Hranueli D, Toman Z (eds) Genetics of industrial microorganisms–86. Pliva, Zagreb, pp 177–184Google Scholar
  43. Nakano MM, Mashiko H, Ogawara H (1984) Cloning of the kanamycin resistance gene from a kanamycin-producing Streptomyces species. J Bacteriol 157: 79–83PubMedGoogle Scholar
  44. Noller HF (1984) Structure of ribosomal RNA. Annu Rev Biochem 53: 119–162PubMedCrossRefGoogle Scholar
  45. Pestka S, Vince R, LeMahieu R, Weiss F, Fern L, Unowsky J (1976) Induction of erythromycin resistance in Staphylococcus aureus by erythromycin derivatives. Antimicrob Agents Chemother 9: 128–130PubMedGoogle Scholar
  46. Piendl W, Böck A (1982) Ribosomal resistance in the gentamicin producer organism Micromonospora purpurea. Antimicrob Agents Chemother 22: 231–236PubMedGoogle Scholar
  47. Piendl W, Böck A, Cundliffe E (1984) Involvement of 16S ribosomal RNA in resistance of the aminoglycoside-producers Streptomyces tenjimariensis, Streptomyces tenebrarius and Micromonospora purpurea. Mol Gen Genet 197: 24–29PubMedCrossRefGoogle Scholar
  48. Ranzini AC, Dubin DT (1983) The “erythromycin-resistance” methylated sequence of Staphylococcus aureus ribosomal RNA. Plasmid 10: 293–295PubMedCrossRefGoogle Scholar
  49. Rasmussen JL, Odelson DA, Macrina FL (1986) Complete nucleotide sequence and transcription of ermF, a macrolide-lincosamide-streptogramin B resistance determinant from Bacteroides fragilis. J Bacteriol 168: 523–533PubMedGoogle Scholar
  50. Roberts AN, Hudson GS, Brenner S (1985) An erythromycin-resistance gene from an erythromycin-producing strain of Arthrobacter sp. Gene 35: 259–270PubMedCrossRefGoogle Scholar
  51. Saito T, Hashimoto H, Mitsuhashi S (1970) Macrolide resistance in Staphylococcus aureus. Isolation of a mutant in which leucomycin is an active inducer. Jpn J Microbiol 14: 473–478PubMedGoogle Scholar
  52. Schmidt FJ, Thompson J, Lee K, Dijk J, Cundliffe E (1981) The binding site for ribosomal protein L11 within 23S ribosomal RNA of Escherichia coli. J Biol Chem 256: 12301–12305PubMedGoogle Scholar
  53. Shivakumar AG, Dubnau D (1981) Characterization of a plasmid-encoded ribosome methylase associated with macrolide resistance. Nucleic Acids Res 9: 2549–2562PubMedCrossRefGoogle Scholar
  54. Shivakumar AG, Hahn J, Dubnau D (1979) Studies on the synthesis of plasmid-coded proteins and their control in Bacillus subtilis minicells. Plasmid 2: 279–289PubMedCrossRefGoogle Scholar
  55. Shivakumar AG, Hahn J, Grandi G, Kozlov Y, Dubnau D (1980) Posttranscriptional regulation of an erythromycin resistance protein specified by plasmid pE 194. Proc Natl Acad Sci USA 77: 3903–3907PubMedCrossRefGoogle Scholar
  56. Skeggs PA, Thompson J, Cundliffe E (1985) Methylation of 16S ribosomal RNA and resistance to aminoglycoside antibiotics in clones of Streptomyces lividans carrying DNA from Streptomyces tenjimariensis. Mol Gen Genet 200: 415–421PubMedCrossRefGoogle Scholar
  57. Skeggs PA, Holmes DJ, Cundliffe E (1987) Cloning of aminoglycoside-resistance determinants from Streptomyces tenebrarius and comparison with related genes from other actinomycetes. J Gen Microbiol 133: 915–923PubMedGoogle Scholar
  58. Skinner RH, Cundliffe E (1982) Dimethylation of adenine and the resistance of Streptomyces erythraeus to erythromycin. J Gen Microbiol 128: 2411–2416Google Scholar
  59. Skinner R, Cundliffe E, Schmidt FJ (1983) Site of action of a ribosomal RNA methylase responsible for resistance to erythromycin and other antibiotics. J Biol Chem 258: 12702–12706PubMedGoogle Scholar
  60. Sugiyama M, Nimi O, Nomi R (1980) Susceptibility of protein synthesis to neomycin in neomycin-producing Streptomyces fradiae. J Gen Microbiol 121: 477–478PubMedGoogle Scholar
  61. Tanaka T, Weisblum B (1974) Mutant of Staphylococcus aureus with lincomycin — and carbomycin — inducible resistance to erythromycin. Antimicrob Agents Chemother 5: 538–540PubMedGoogle Scholar
  62. Teraoka H, Tanaka K (1974) Properties of ribosomes from Streptomyces erythreus and Streptomyces griseus. J Bacteriol 120: 316–321PubMedGoogle Scholar
  63. Thakker-Varia S, Ranzini AC, Dubin DT (1985) Ribosomal RNA methylation in Staphylococcus aureus and Escherichia coli: effect of the “MLS” (erythromycin resistance) methylase. Plasmid 14: 152–161PubMedCrossRefGoogle Scholar
  64. Thompson CJ, Ward JM, Hopwood DA (1980) DNA cloning in Streptomyces: resistance genes from antibiotic-producing species. Nature 286: 525–527PubMedCrossRefGoogle Scholar
  65. Thompson CJ, Skinner RH, Thompson J, Ward JM, Hopwood DA, Cundliffe E (1982) Biochemical characterization of resistance determinants cloned from antibiotic-producing streptomycetes. J Bacteriol 151: 678–685PubMedGoogle Scholar
  66. Thompson J, Cundliffe E (1981) Purification and properties of an RNA methylase produced by Streptomyces azureus and involved in resistance to thiostrepton. J Gen Microbiol 124: 291–297Google Scholar
  67. Thompson J, Cundliffe E, Stark M (1979) Binding of thiostrepton to a complex of 23S rRNA with ribosomal protein L11. Eur J Biochem 98: 261–265PubMedCrossRefGoogle Scholar
  68. Thompson J, Schmidt F, Cundliffe E (1982) Site of action of a ribosomal RNA methylase conferring resistance to thiostrepton. J Biol Chem 257: 7915–7917PubMedGoogle Scholar
  69. Thompson J, Rae S, Cundliffe E (1984) Coupled transcription-translation in extracts of Streptomyces lividans. Mol Gen Genet 195: 39–43PubMedCrossRefGoogle Scholar
  70. Thompson J, Skeggs PA, Cundliffe E (1985) Methylation of 16S ribosomal RNA and resistance to the aminoglycoside antibiotics gentamicin and kanamycin determined by DNA from the gentamicin-producer, Micromonospora purpurea. Mol Gen Genet 201: 168–173PubMedCrossRefGoogle Scholar
  71. Thompson J, Cundliffe E, Dahlberg AE (1988) Site-directed mutagenesis of Escherichia coli 23S ribosomal RNA at position 1067 within the GTP hydrolysis centre. J Mol Biol 203: 457–465PubMedCrossRefGoogle Scholar
  72. Uchiyama H, Weisblum B (1985) N-methyl transferase of Streptomyces erythraeus that confers resistance to the macrolide-lincosamide-streptogramin B antibiotics-amino acid sequence and its homology to cognate R-factor enzymes from pathogenic bacilli and cocci. Gene 38: 103–110PubMedCrossRefGoogle Scholar
  73. Weaver JR, Pattee PA (1964) Inducible resistance to erythromycin in Staphylococcus aureus. J Bacteriol 88: 574–580PubMedGoogle Scholar
  74. Weisblum B (1975) Altered methylation of ribosomal ribonucleic acid in erythromycin-resistant Staphylococcus aureus. In: Schlessinger D (ed) Microbiology -1974. American Society for Microbiology, Washington DC, pp 199–206Google Scholar
  75. Weisblum B (1985) Inducible resistance to macrolides, lincosamides and streptogramin type B antibiotics: the resistance phenotype, its biological diversity, and structural elements that regulate expression — A review. J Antimicrob Chemother [Suppl A] 16: 63–90Google Scholar
  76. Yamamoto H, Hotta K, Okami Y, Umezawa H (1981) Ribosomal resistance of an istamycin producer, Streptomyces tenjimariensis, to aminoglycoside antibiotics. Biochem Biophys Res Commun 100: 1396–1401PubMedCrossRefGoogle Scholar
  77. Yamamoto H, Hotta K, Okami Y, Umezawa H (1982) Mechanism of resistance to amino-glycoside antibiotics in nebramycin-producing Streptomyces tenebrarius. J Antibiot [Tokyo] 35: 1020–1025Google Scholar
  78. Yanofsky C (1981) Attenuation in the control of expression of bacterial operons. Nature 289: 751–758PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1989

Authors and Affiliations

  • E. Cundliffe

There are no affiliations available

Personalised recommendations