Resistance to Trimethoprim

  • L. P. Elwell
  • M. E. Fling
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 91)


Trimethoprim (2,4-diamino-5-(3′,4′5′-trimethoxybenzyl)pyrimidine) is one of a series of compounds first fully described by Roth et al. (1962). These compounds possess both antimalarial and antibacterial activity, the former activity exemplified by pyrimethamine and the latter activity by trimethoprim (Tp). Tp is a potent inhibitor of dihydrofolate reductase (5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase EC; DHFR), an enzyme that catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, a cofactor required for the metabolism of some amino acids, purines and thymidine. The structure of trimethoprim and one of its clinically used structural analogs, tetroxoprim, is shown in Fig. 1. Tp has a several thousand-fold higher affinity for bacterial DHFR than for mammalian DHFR; the bacterial synthesis of tetrahydrofolate is preferentially diminished as a consequence of this selective binding (Burchall 1973; Hitchings 1973).


Antimicrob Agent Dihydrofolate Reductase Resistance Determinant Phage Type aadA Gene 
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  1. Acar JF, Goldstein FW (1982) Genetic aspects and epidemiologic implications of resistance to trimethoprim. Rev Infect Dis 4: 270–275PubMedGoogle Scholar
  2. Albritton WL, Brunton JL, Slaney L, MacLean I (1982) Plasmid-mediated sulfonamide resistance in Haemophilus ducreyi. Antimicrob Agents Chemother 21: 159–165PubMedGoogle Scholar
  3. Alon U, Davidai G, Berant M, Merzbach D (1987) Five-year survey of changing patterns of susceptibility of bacterial uropathogens to trimethoprim-sulfamethoxazole and other antimicrobial agents. Antimicrob Agents Chemother 31: 126–128PubMedGoogle Scholar
  4. Amyes SGB (1986) Epidemiology of trimethoprim resistance. J Antimicrob Chemother [Suppl C] 18: 215–221Google Scholar
  5. Amyes SGB, Smith JT (1974) R-factor trimethoprim resistance mechanism: an insusceptible target site. Biochem Biophys Res Commun 58: 412–418PubMedGoogle Scholar
  6. Amyes SGB, Doherty CJ, Young HK (1986) High-level trimethoprim resistance in urinary bacteria. Eur J Clin Microbiol 5: 287–291PubMedGoogle Scholar
  7. Anderson DM (1980) Plasmid studies of Salmonella typhimurium phage type 179 resistant to ampicillin, tetracycline, sulphonamides and trimethoprim. J Hyg 85: 293–300Google Scholar
  8. Archer GL, Coughter JP, Johnston JL (1986) Plasmid-encoded trimethoprim resistance in staphylococci. Antimicrob Agents Chemother 29: 733–740PubMedGoogle Scholar
  9. Averett DR, Roth B, Burchall JJ, Baccanari DP (1979) Dihydrofolate reductase from Neisseria sp. Antimicrob Agents Chemother 15: 428–435PubMedGoogle Scholar
  10. Bachmann BJ (1983) Linkage map of Escherichia coli K-12, edition 7. Microbiol Rev 47: 180–230PubMedGoogle Scholar
  11. Bagdasarian M, Lurz R, Ruckert B, Franklin FCH, Bagdasarian MM, Frey J, Timmis KN (1981) Specific-purpose plasmid cloning vectors. II. Broad host range, high copy number RSF1010-derived vectors, and a host-vector system for gene cloning in Pseudomonas. Gene 16: 237–247PubMedGoogle Scholar
  12. Barker H, Healing D, Hutchison JG (1972) Characteristics of some co-trimoxazole-resistant Enterobacteriaceae from infected patients. J Clin Pathol 25: 1086–1088PubMedGoogle Scholar
  13. Barner HD, Cohen SS (1959) Virus-induced acquisition of metabolic function. IV. Thymidylate synthetase in thymine-requiring Escherichia coli infected by T2 and T5 bacteriophages. J Biol Chem 234: 2987–2991PubMedGoogle Scholar
  14. Barth PT, Datta N (1977) Two naturally occurring transposons indistinguishable from Tn7. J Gen Microbiol 102: 129–134PubMedGoogle Scholar
  15. Barth PT, Grinter NJ (1974) Comparison of the deoxyribonucleic acid molecular weights and homologies of plasmids conferring linked resistance to streptomycin and sulfonamides. J Bacteriol 120: 618–630PubMedGoogle Scholar
  16. Barth PT, Datta N, Hedges RW, Grinter NJ (1976) Transposition of a deoxyribonucleic acid sequence encoding trimethoprim and streptomycin resistances from R483 to other replicons. J Bacteriol 125: 800–810PubMedGoogle Scholar
  17. Bertino JB, Stacey KA (1966) A suggested mechanism for the selective procedure for iso-lating thymine requiring mutants of Escherichia coli. Biochem J 101: 32C - 33CPubMedGoogle Scholar
  18. Breeze AS, Sims P, Stacey KA (1975) Trimethoprim-resistant mutants of E. coli K12: pre-liminary genetic mapping. Genet Res 25: 207–214PubMedGoogle Scholar
  19. Breitman TR, Bradford RM (1967) The absence of deoxyriboaldolase activity in a thymineless mutant of Escherichia coli strain 15: a possible explanation for the low thymine requirement of some thymineless strains. Biochim Biophys Acta 138: 217–220PubMedGoogle Scholar
  20. Brisson N, Hohn T (1984) Nucleotide sequence of the dihydrofolate-reductase gene borne by the plasmid R67 and conferring methotrexate resistance. Gene 28: 271–275PubMedGoogle Scholar
  21. Brumfitt W, Hamilton-Miller JMT, Wood A (1983) Evidence for a slowing in trimethoprim resistance during 1981— a comparison with earlier years. J Antimicrob Chemother 11: 503–509PubMedGoogle Scholar
  22. Brunton J, Clare D, Meier MA (1986) Molecular epidemiology of antibiotic resistance plasmid of Haemophilus species and Neisseria gonorrhoeae. Rev Infect Dis 8: 713–724PubMedGoogle Scholar
  23. Bryan LE, van den Elzen HM, Tseng JT (1972) Transferable drug resistance in Pseudomo-nas aeruginosa. Antimicrob Agents Chemother 1: 22–29PubMedGoogle Scholar
  24. Burchall JJ (1973) Mechanism of action of trimethoprim-sulfamethoxazole — II. J Infect Dis 128: S437–441Google Scholar
  25. Burchall JJ, Elwell LP, Fling ME (1982) Molecular mechanisms of resistance to trimethoprim. Rev Infect Dis 4: 246–254PubMedGoogle Scholar
  26. Cameron FH, Groot-Obbink DJ, Ackerman VP, Hall RM (1986) Nucleotide sequence of the AAD(2’) aminoglycoside adenylyltransferase determinant aadB. Evolutionary relationship of this region with those surrounding aadA in R538–1 and dhfrll in R388. Nucleic Acids Res 14: 8625–8635PubMedGoogle Scholar
  27. Campbell IG, Mee BJ (1987) Mapping of trimethoprim resistance genes from epidemiologically relate plasmids. Antimicrob Agents Chemother 31: 1440–1441PubMedGoogle Scholar
  28. Campbell IG, Mee BJ, Nikoletti SM (1986) Evolution and spread of IncFIV plasmids conferring resistance to trimethoprim. Antimicrob Agents Chemother 29: 807–813PubMedGoogle Scholar
  29. Chatkaeomorakot A, Echeverria P, Taylor DN, Seriwatana J, Leksomboon U (1987) Trimethoprim resistant Shigella and enterotoxigenic Escherichia coli strains in children in Thailand. Pediatr Infect Dis 6: 735–739Google Scholar
  30. Chattopadhyay BL (1977) Co-trimoxazole resistant Staphylococcus aureus in hospital practice. J Antimicrob Chemother 3: 371–374PubMedGoogle Scholar
  31. Chinault AC, Blakesley VA, Roessler E, Willis DG, Smith CA, Cook RG, Fenwick RG Jr (1986) Characterization of transferable plasmids from Shigellaflexneri 2a that confer resistance to trimethoprim, streptomycin, and sulfonamides. Plasmid 15: 119–131PubMedGoogle Scholar
  32. Chirnside ED, Emmerson AM, Smith JT (1985) A follow-up survey of transferable, plasmid-encoded trimethoprim resistance in a general hospital (1975–1983). J Antimicrob Chemother 16: 419–434PubMedGoogle Scholar
  33. Chun D, Seol SY, Suh MH (1981) Transferable resistance to trimethoprim in Shigella. J Infect Dis 143: 742PubMedGoogle Scholar
  34. Coleman DC, Pomeroy H, Estridge JK, Keane CT, Cafferkey MT, Hone R, Foster TJ (1985) Susceptibility to antimicrobial agents and analysis of plasmids in gentamicinand methicillin-resistant Staphylococcus aureus from Dublin hospitals. J Med Microbiol 20: 157–167PubMedGoogle Scholar
  35. Coughter JP, Johnston AL, Archer GL (1987) Characterization of a staphylococcal trimethoprim resistance gene and its product. Antimicrob Agents Chemother 31: 1027–1032PubMedGoogle Scholar
  36. Datta N, Hughes VM, Nugent ME, Richards H (1979) Plasmids and transposons and their stability and mutability in bacteria isolated during an outbreak of hospital infection. Plasmid 2: 182–196PubMedGoogle Scholar
  37. Datta N, Nugent M, Richards H (1980 b) Transposons encoding trimethoprim or gentamicin resistance in medically important bacteria. Cold Spring Harbor Symposium Quantitive Biology 45(1):45–51Google Scholar
  38. Dupont MJ, Jouvenot M, Gouetdic G, Michel-Briand Y (1985) Development of plasmidmediated resistance in Vibrio cholerae during treatment with trimethoprim-sulfamethoxazole. Antimicrob Agents Chemother 27: 280–281PubMedGoogle Scholar
  39. Elwell LP, Wilson HR, Knick VB, Keith BR (1986) In vitro and in vivo efficacy of the com-bination trimethoprim-sulfamethoxazole against clinical isolates of methicillin-resis-tant Staphylococcus aureus. Antimicrob Agents Chemother 29: 1092–1094PubMedGoogle Scholar
  40. Farrar WE (1985) Antibiotic resistance in developing countries. J Infect Dis 152: 1103–1106PubMedGoogle Scholar
  41. Fleming MP, Datta N, Gruneberg RN (1972) Trimethoprim resistance determined by R factors. Br Med J 1: 726–728PubMedGoogle Scholar
  42. Flensburg J, Skold O (1984) Regulatory changes in the formation of chromosomal dihy-drofolate reductase causing resistance to trimethoprim. J Bacteriol 159: 184–190PubMedGoogle Scholar
  43. Flensburg J, Skold O (1987) Massive overproduction of dihydrofolate reductase in bacteria as a response to the use of trimethoprim. Eur J Biochem 162: 473–476PubMedGoogle Scholar
  44. Flensburg J, Steen R (1986) Nucleotide sequence analysis of the trimethoprim resistant dihydrofolate reductase encoded by R plasmid R751. Nucleic Acids Res 14: 5933PubMedGoogle Scholar
  45. Fling ME, Elwell LP (1980) Protein expression in Escherichia coli minicells containing recombinant plasmids specifying trimethoprim-resistant dihydrofolate reductases. J Bacteriol 141: 779–785PubMedGoogle Scholar
  46. Fling ME, Richards C (1983) The nucleotide sequence of the trimethoprim-resistant dihydrofolate reductase gene harbored by Tn7. Nucleic Acids Res 11: 5147–5158PubMedGoogle Scholar
  47. Fling ME, Walton L, Elwell LP (1982) Monitoring of plasmid-encoded, trimethoprim-resistant dihydrofolate reductase genes: detection of a new resistant enzyme. Antimicrob Agents Chemother 22: 882–888PubMedGoogle Scholar
  48. Fling ME, Kopf J, Richards C (1985) Nucleotide sequence of the transposon Tn7 gene encoding an aminoglycoside-modifying enzyme, 3“ (9)-o-nucleotidyl transferase. Nucleic Acids Res 13: 7095–7106PubMedGoogle Scholar
  49. Fling ME, Kopf J, Richards C (1988) Characterization of plasmid pAZ1 and the type III dihydrofolate reductase gene. Plasmid 19: 30–38PubMedGoogle Scholar
  50. Freisheim JH, Bitar KG, Reddy AV, Blankenship DT (1978) Dihydrofolate reductase from amethopterin-resistant Lactobacillus casei: sequences of the cyanogen bromide peptides and complete sequences of the enzyme. J Biol Chem 253: 6437–6444PubMedGoogle Scholar
  51. Frost JA, Willshaw GA, Barclay EA, Rowe B, Lemmens P (1985) Plasmid characterization of drug-resistant Shigella dysenteriae 1 from an epidemic in Central Africa. J Hyg 94: 163–172Google Scholar
  52. Gillespie MT, Skurray RA (1986) Plasmids in multiresistant Staphylococcus aureus. Microbiol Sci 3: 53–58PubMedGoogle Scholar
  53. Gilligan PH, Gage PA, Welch DF, Muszynski MJ, Wait KR (1987) Prevalence of thymidine-dependent Staphylococcus aureus in patients with cystic fibrosis. J Clin Microbiol 25: 1258–1261PubMedGoogle Scholar
  54. Goldberger RF (1974) Autogenous regulation of gene expression. Science 183: 810–816PubMedGoogle Scholar
  55. Goldstein FW, Gutmann L, Williamson R, Collatz E, Acar JF (1983 a) In vivo and in vitro emergence of simultaneous resistance to both ß-lactam and aminoglycoside antibiotics in a strain of Serratia marcescens. Ann Microbiol (Paris) 134(A):329–337Google Scholar
  56. Gosti-Testu F, Norris V, Brevet J (1983) Restriction map of Tn7. Plasmid 10: 96–99PubMedGoogle Scholar
  57. Gouy M, Gautier C (1982) Codon usage in bacteria: correlation with gene expressivity. Nucleic Acids Res 10: 7055–7074PubMedGoogle Scholar
  58. Grey D, Hamilton-Miller JMT, Brumfitt W (1979) Incidence and mechanisms of resistance to trimethoprim in clinically isolated gram-negative bacteria. Chemother 25: 147–156Google Scholar
  59. Gross RJ, Threlfall EJ, Ward LR, Rowe B (1984) Drug resistance in Shigella dysenteriae, S. flexneri, and S. boydii in England and Wales: increasing incidence of resistance to trimethoprim. Br Med J 288: 784–786Google Scholar
  60. Gruneberg RN (1984) Antibiotic sensitivities of urinary pathogens, 1971–1982. J Antimicrob Chemother 14: 17–23PubMedGoogle Scholar
  61. Guerrant RL, Wood SJ, Krongaard L, Reid RA, Hodge RH (1981) Resistance among fecal flora of patients taking sulfamethoxazole-trimethoprim or trimethoprim alone. Antimicrob Agents Chemother 19: 33–38PubMedGoogle Scholar
  62. Gurwith MJ, Brunton JL, Lank BA, Harding GKM, Ronald AR (1979) A prospective controlled investigation of prophylactic trimethoprim/sulfamethoxazole in hospitalized granulocytopenic patients. Am J Med 66: 248–256PubMedGoogle Scholar
  63. Gutmann L, Williamson R, Moreau N, Kitzis MD, Collatz E, Acar JF, Goldstein FW (1985) Cross-resistance to nalidixic acid, trimethoprim, and chloramphenicol associated with alterations in outer membrane proteins of Klebsiella, Enterobacter, and Serratia. J Infect Dis 151: 501–507PubMedGoogle Scholar
  64. Hamilton-Miller JMT (1979) Mechanisms and distribution of bacterial resistance to diamino-pyrimidines and sulfonamides. J Antimicrob Chemother [Suppl B] 5: 61–73Google Scholar
  65. Hedges RW (1987) A plasmid of group Q which confers resistance to trimethoprim and sulfonamides. Microbiol Immunol 31: 1113–1115PubMedGoogle Scholar
  66. Hitchings GH (1973) Mechanism of action of trimethoprim-sulfamethoxazole–I. J Infect Dis 128: S433–436Google Scholar
  67. Hollingshead S, Vapnek D (1985) Nucleotide sequence analysis of a gene encoding a strep-tomycin/spectinomycin adenyltransferase. Plasmid 13: 17–30PubMedGoogle Scholar
  68. Howden R (1981) A new medium for isolation of Staphylococcus aureus, including thymine requiring strains, from sputum. Med Lab Sci 38: 29–33PubMedGoogle Scholar
  69. Huovinen P, Pulkkinen L, Toivanen P (1983) Transferable trimethoprim resistance in three Finnish hospitals. J Antimicrob Chemother 12: 249–256PubMedGoogle Scholar
  70. Huovinen P, Pulkkinen L, Helin HL, Makila M, Toivanen P (1986) Emergence of trimethoprim resistance in relation to drug consumption in a Finnish hosital from 1971 through 1984. Antimicrob Agents Chemother 29: 73–76PubMedGoogle Scholar
  71. Joyner SS, Fling ME, Stone D, Baccanari DP (1984) Characterization of an R-plasmid di-hydrofolate reductase with a monomeric structure. J Biol Chem 259: 5851–5856PubMedGoogle Scholar
  72. Koch AL (1981) Evolution of antibiotic resistance gene function. Microbiol Rev 45: 355–378PubMedGoogle Scholar
  73. Korfmann G, Ludtke W, van Treeck U, Wiedemann B (1983) Dissemination of streptomycin and sulfonamide resistant by plasmid pBP1 in Escherichia coli. Eur J Clin Microbiol 2: 463–468PubMedGoogle Scholar
  74. Kraft CA, Timbury MC, Platt DJ (1986) Distribution and genetic location of Tn7 in trimethoprim-resistant Escherichia coli. J Med Microbiol 22: 125–131PubMedGoogle Scholar
  75. Labigne-Roussel A, Witchitz J, Courvalin P (1982) Modular evolution of disseminated Inc 7-M plasmids encoding gentamicin resistance. Plasmid 8: 215–231PubMedGoogle Scholar
  76. Lacey RW (1975) Antibiotic resistance plasmids of Staphylococcus aureus and their clinical importance. Bacteriol Rev 39: 1–32PubMedGoogle Scholar
  77. Lacey RW, Kruczenyk (1986) Epidemiology of antibiotic resistance in Staphylococcus aureus. J Antimicrob Chemother 18 [Suppl C]: 207–214PubMedGoogle Scholar
  78. Leary JV, Trollinger DB (1985) Identification of an indigenous plasmid carrying a gene for trimethoprim resistance in Pseudomonas syringae pv. glycinea. Mol Gen Genet 201: 485–486Google Scholar
  79. Lewis EL, Lacey RW (1973) Present significance of resistance to trimethoprim and sulphonamides in coliforms, Staphylococcus aureus, and Streptococcus faecalis. J Clin Pathol 26: 175–180PubMedGoogle Scholar
  80. Lichtenstein C, Brenner S (1981) Site-specific properties of Tn7 transposition into the E. coli chromosome. Mol Gen Genet 183: 380–387PubMedGoogle Scholar
  81. Lichtenstein C, Brenner S (1982) Unique insertion site of Tn7 in the E. coli chromosome. Nature 297: 601–603PubMedGoogle Scholar
  82. Ling J, Chau PY (1984) Plasmids mediating resistance to chloramphenicol, trimethoprim, and ampicillin in Salmonella typhi strains isolated in the Southeast Asian region. J Infect Dis 149: 652PubMedGoogle Scholar
  83. Lomax MS, Greenberg GR (1968) Characteristics of the deo operon: role in thymine utilization and sensitivity to deoxyribonucleosides. J Bacteriol 96: 501–514PubMedGoogle Scholar
  84. Lopez-Brea M, Collado L, Vincente F, Perez-Diaz JC (1983) Increasing antimicrobial resistance of Shigella sonnet. J Antimicrob Chemother 11: 598PubMedGoogle Scholar
  85. Lyon BR, Skurray R (1987) Antimicrobial resistance of Staphylococcus aureus: genetic basis. Microbiol Rev 51: 88–134PubMedGoogle Scholar
  86. Macaden R, Bhat P (1985) The changing pattern of resistance to ampicillin and co-trimox-azole in Shigella serotypes in Bangalore, southern India. J Infect Dis 152: 1348PubMedGoogle Scholar
  87. Maskell R, Okubadejo OA, Payne RH, Pead L (1977) Human infections with thymine-requiring bacteria. J Med Microbiol 11: 33–45Google Scholar
  88. Matsushita S, Kudoh Y, Ohashi M (1984) Transferable resistance to the vibriostatic agent 2,4-diamino-6,7-diisopropyl-pteridine (0/129) in Vibrio cholerae. Microbiol Immunol 28: 1159–1162PubMedGoogle Scholar
  89. Matthews DA, Alden RA, Bolin JT, Freer ST, Hamlin R, Xuong N, Kraut J, Poe M, Williams M, Hoogsteen K (1977) Dihydrofolate reductase: X-ray structure of the binary complex with methotrexate. Science 197: 452–455PubMedGoogle Scholar
  90. Matthews DA, Smith SL, Baccanari DP, Burchall JJ, Oatley SJ, Kraut J (1986) Crystal structure of a novel trimethoprirn-resistant dihydrofolate reductase specified in Escherichia coli by R-plasmid R67. Biochemistry 25: 4194–4204PubMedGoogle Scholar
  91. Mayer KH, Fling ME, Hopkins JD, O’Brien TF (1985) Trimethoprim resistance in multiple genera of Enterobacteriaceae at a U.S. hospital: spread of the type II dihydrofolate reductase gene by a single plasmid. J Infect Dis 151: 783–789PubMedGoogle Scholar
  92. McCuen RW, Sirotnak FM (1974) Hyperproduction of dihydrofolate reductase in Diplococcus pneumoniae by mutation in the structural gene. The absence of an effect on other enzymes of folate coenzyme biosynthesis. Biochim Biophys Acta 338: 540–544Google Scholar
  93. McKown RL, Waddell CS, Arciszewska LK, Craig NL (1987) Identification of a transposon Tn7-dependent DNA-binding activity that recognizes the ends of Tn7. Proc Natl Acad Sci USA 84: 7807–7811PubMedGoogle Scholar
  94. Mee BJ, Nikoletti SM (1983) Plasmids encoding trimethoprim resistance in bacterial isolates from man and pigs. J Appl Bacteriol 54: 225–235PubMedGoogle Scholar
  95. Murray BE, Rensimer ER, DuPont HL (1982) Emergence of high-level trimethoprim resistance in fecal Escherichia coli during oral administration of trimethoprim or trimethoprim-sulfamethoxazole. N Engl J Med 306: 130–135PubMedGoogle Scholar
  96. Murray BE, Alvarado T, Kim KH, Vorachit M, Jayanetra P, Levine MM, Prenzel I, Fling M, Elwell L, McCracken GH, Madrigal G, Odio C, Trabulsi LR (1985) Increasing resistance to trimethoprim-sulfamethoxazole among isolates of Escherichia coli in developing countries. J Infect Dis 152: 1107–1113PubMedGoogle Scholar
  97. Nakhla LS (1972) Resistance of Staphylococcus aureus to sulfamethoxazole and trimethoprim. J Clin Pathol 25: 708–712PubMedGoogle Scholar
  98. Novak P, Stone D, Burchall JJ (1983) R plasmid dihydrofolate reductase with a dimeric subunit structure. J Biol Chem 258: 10956–10959PubMedGoogle Scholar
  99. Obaseiki-Ebor EE, Abiodun PO, Emina PA (1986) Fecal Escherichia coli mediating transferable multi-antibiotic resistance and undesirable extra-chromosomal genes. Ann Trop Paediatr 6: 283–286PubMedGoogle Scholar
  100. O’Brien TF (1987) Resistance of bacteria to antibacterial agents: report of task force 2. Rev Infect Dis 9 [Suppl 3]: S244 - S260PubMedGoogle Scholar
  101. Okada T, Yanagisawa K, Ryan FJ (1960) Elective production of thymine-less mutants. Nature 188: 340–341PubMedGoogle Scholar
  102. Okubadejo OA, Maskell RM (1973) Thymine-requiring mutants of Proteus mirabilis selected by co-trimoxazole in vivo. J Gen Microbiol 77: 533–535PubMedGoogle Scholar
  103. Ouartsi A, Borowski D, Brevet J (1985) Genetic analysis of Tn7 transposition. Mol Gen Genet 198: 221–227PubMedGoogle Scholar
  104. Palenque E, Otero JR, Noriega AR (1983) High prevalence of non-epidemic Shigella sonnei resistant to co-trimoxazole. J Antimicrob Chemother 11: 196–198PubMedGoogle Scholar
  105. Pancoast SJ, Hyams DM, Neu HC (1980) Effect of trimethoprim and trimethoprim-sulfamethoxazole on development of drug-resistant vaginal and fecal floras. Antimicrob Agents Chemother 17: 263–268PubMedGoogle Scholar
  106. Paniker CKJ, Vimala KN, Bhat P, Stephen S (1978) Drug resistant shigellosis in south India. Indian J Med Res 68: 413–417PubMedGoogle Scholar
  107. Paramasivan CN, Subramanian S, Shanmugasundaram N (1977) Antimicrobial resistance and incidence of R factor among Salmonella isolated from patients with enteric fever and other clinical conditions in Madras, India (1975–1976). J Infect Dis 13: 796–800Google Scholar
  108. Pattishall KH, Acar J, Burchall JJ, Goldstein FW, Harvey RJ (1977) Two distinct types of trimethoprim-resistant dihydrofolate reductase specified by R-plasmids of different compatibility groups. J Biol Chem 252: 2319–2323PubMedGoogle Scholar
  109. Pulkkinen L, Huovinen P, Vuorio E, Toivanen P (1984) Characterization of trimethoprim resistance by use of probes specific for transposon Tn7. Antimicrob Agents Chemother 26: 82–86PubMedGoogle Scholar
  110. Richards H, Datta N (1982) Plasmids and transposons acquired by Salmonella typhi in man. Plasmid 8: 9–14PubMedGoogle Scholar
  111. Richards H, Nugent M (1979) The incidence and spread of transposon 7. In: Timmis KN, Puhler A (eds) Plasmids of medical, environmental and commercial importance. Elsevier, Amsterdam, pp 195–198Google Scholar
  112. Richardson JF (1983) Frequency of resistance to trimethoprim among isolates of Staphylococcus epidermidis and Staphylococcus saprophyticus. J Antimicrob Chemother 11: 163–167PubMedGoogle Scholar
  113. Rogers M, Ekaterinaki N, Nimmo E, Sherratt D (1986) Analysis of Tn7 transposition. Mol Gen Genet 205: 550–556PubMedGoogle Scholar
  114. Rosenberg M, Court D (1979) Regulatory sequences involved in the promotion and termination of RNA transcription. Annu Rev Genet 13: 319–353PubMedGoogle Scholar
  115. Rotger R, Rubio F, Nombela C (1986) A multi-resistance plasmid isolate from commensal Neisseria species is closely related to the enterobacterial plasmid RSF1010. J Gen Microbiol 132: 2491–2496PubMedGoogle Scholar
  116. Roth B, Falco EA, Hitchings GH (1962) 5-benzyl-2,4-diaminopyrimidines as antibacterial agents. I. Synthesis and antibacterial activity in vitro. J Med Pharm Chem 5: 1103–1123Google Scholar
  117. Rowe B, Threlfall EJ, Ward LR, Ashley AS (1979) International spread of multiresistant strains of Salmonella typhimurium phage types 204 and 193 from Britain to Europe. Vet Rec 105: 468–469PubMedGoogle Scholar
  118. Saad AF, Farrar WE Jr (1977) Antimicrobial resistance and R factors in Salmonella isolated from humans and animals in Georgia and South Carolina. South Med J 70: 305–308PubMedGoogle Scholar
  119. Scudamore RA, Goldner M (1982) Limited contribution of the outer-membrane penetration barrier towards intrinsic antibiotic resistance of Pseudomonas aeruginosa. Can J Microbiol 28: 169–175PubMedGoogle Scholar
  120. Sellers J (1982) Frequency and transmissibility of trimethoprim resistance in enterobacteria from urinary infections. Scand J Infect Dis 14: 157–158PubMedGoogle Scholar
  121. Shahid NS, Rahaman MM, Haider K, Banu H, Rahman N (1985) Changing pattern of resistant shiga bacillus (SHIGELLA DYSENTERIAE type I) and Shigella flexneri in Bangladesh. J Infect Dis 152: 1114–1119PubMedGoogle Scholar
  122. Shapiro JA (1983) Mobile genetic elements. Academic Press, New YorkGoogle Scholar
  123. Shapiro JA, Sporn P (1977) Tn402: a new transposable element determining trimethoprim resistance that inserts in bacteriophage lambda. J Bacteriol 129: 1632–1635PubMedGoogle Scholar
  124. Sheldon R (1977) Altered dihydrofolate reductase in fol regulatory mutants of Escherichia coli K12. Mol Gen Genet 151: 215–219PubMedGoogle Scholar
  125. Sheldon R, Brenner S (1976) Regulatory mutants of dihydrofolate reductase in Escherichia coli K12. Mol Gen Genet 147: 91–97PubMedGoogle Scholar
  126. Sirotnak FM, McCuen RW (1973) Hyperproduction of dihydrofolate reductase in Diplococcus pneumoniae after mutation in the structural gene. Evidence for an effect at the level of transcription. Genetics 74: 543–556PubMedGoogle Scholar
  127. Sirotnak FM, Hachtel SL, Williams WA (1969) Increased dihydrofolate reductase synthesis in Diplococcus pneumoniae following translatable alteration of the structural gene. II. Individual and dual effects on the properties and rate of synthesis of the enzyme. Genetics 61: 313–326PubMedGoogle Scholar
  128. Skold O, Widh A (1974) A new dihydrofolate reductase with low trimethoprim sensitivity induced by an R factor mediating high resistance to trimethoprim. J Biol Chem 249: 4324–4325PubMedGoogle Scholar
  129. Smith DR, Calvo JM (1979) Regulation of dihydrofolate reductase synthesis in Escherichia coli. Mol Gen Genet 175: 31–38PubMedGoogle Scholar
  130. Smith DR, Calvo JM (1982) Nucleotide sequence of dihydrofolate reductase genes from trimethoprim-resistant mutants of Escherichia coli. Evidence that dihydrofolate reductase interacts with another essential gene product. Mol Gen Genet 187: 72–78PubMedGoogle Scholar
  131. Smith DR, Rood JL, Bird PI, Sneddon MK, Calvo JM, Morrison JF (1982) Amplification and modification of dihydrofolate reductase in Escherichia coli. Nucleotide sequence offol genes from mutationally altered plasmids. J Biol Chem 257: 9043–9048PubMedGoogle Scholar
  132. Smith GM, Jones P (1984) Effects of deletions in transposon Tn7 on its frequency of transposition. J Bacteriol 157: 962–964PubMedGoogle Scholar
  133. Smith HW (1976) Mutants of Klebsiella pneumoniae resistant to several antibiotics. Nature 259: 307–308PubMedGoogle Scholar
  134. Smith HW, Tucker JF (1976) The virulence of trimethoprim-resistant thymine-requiring strains of Salmonella. J Hyg 76: 97–108Google Scholar
  135. Smith SL, Stone D, Novak P, Baccanari DP, Burchall JJ (1979) R plasmid dihydrofolate reductase with subunit structure. J Biol Chem 254: 6222–6225PubMedGoogle Scholar
  136. Sparham PD, Lobban DI, Speller DC (1978) Isolation of Staphylococcus aureus from sputum in cystic fibrosis. J Clin Pathol 31: 913–918PubMedGoogle Scholar
  137. Stamm WE, Counts GW, Wagner KF, Martin D, Gregory D, McKevitt M, Turck M, Holmes KK (1980) Antimicrobial prophylaxis of recurrent urinary tract infections: a double-blind, placebo-controlled trial. Ann Intern Med 92: 770–775PubMedGoogle Scholar
  138. Steen R, Skold O (1985) Plasmid-borne or chromosomally mediated resistance by Tn7 is the most common response to ubiquitous use of trimethoprim. Antimicrob Agents Chemother 27: 933–937PubMedGoogle Scholar
  139. Stokes A, Lacey RW (1978) Effect of thymidine on activity of trimethoprim and sulfamethoxazole. J Clin Pathol 31: 165–171PubMedGoogle Scholar
  140. Stone D, Smith SL (1979) The amino acid sequence of the trimethoprim-resistant dihydrofolate reductase specified in Escherichia coli by R-plasmid R67. J Biol Chem 254: 10857–10861PubMedGoogle Scholar
  141. Sundstrom L, Vinayagamoorthy T, Skold 0 (1987) Novel type of plasmid-borne resistance to trimethoprim. Antimicrob Agents Chemother 31: 60–66PubMedGoogle Scholar
  142. Swedberg G (1987) Organization of two sulfonamide resistance genes on plasmids of gram-negative bacteria. Antimicrob Agents Chemother 31: 306–311PubMedGoogle Scholar
  143. Swift G, McCarthy BJ, Heffron F (1981) DNA sequence of a plasmid-encoded dihydrofolate reductase. Mol Gen Genet 181: 441–447PubMedGoogle Scholar
  144. Tait RC, Rempel H, Rodriguez RL, Kado CI (1985) The aminoglycoside-resistance operon of the plasmid pSa: nucleotide sequence of the streptomycin-spectinomycin resistance gene. Gene 36: 97–104PubMedGoogle Scholar
  145. Tanner EI, Bullin CH (1974) Thymidine-dependent Escherichia coli infection and some associated laboratory problems. J Clin Path 27: 565–568PubMedGoogle Scholar
  146. Tapsall JW, Wilson E, Harper J (1974) Thymine dependent strains of Escherichia coli selected by trimethoprim-sulphamethoxazole therapy. Pathology 6: 161PubMedGoogle Scholar
  147. Taylor DE, Keystone JS, Devlin HR (1980) Resistance to trimethoprim and other antibiotics in Ontario shigellae. Lancet 1: 476Google Scholar
  148. Taylor DE, Chumpitaz JC, Goldstein F (1985) Variability of IncHI1 plasmids from Salmonella typhi with special reference to Peruvian plasmids encoding resistance to trimethoprim and other antibiotics. Antimicrob Agents Chemother 28: 452–455PubMedGoogle Scholar
  149. Tennent JM, Lyon BR, Gillespie MT, May JW, Skurray RA (1985) Cloning and expression of Staphylococcus aureus plasmid-mediated quaternary ammonium resistance in Escherichia coli. Antimicrob Agents Chemother 27: 79–83PubMedGoogle Scholar
  150. Tennhammar-Ekman B, Skold O (1979) Trimethoprim resistance plasmids of different or-igin encode different drug-resistant dihydrofolate reductases. Plasmid 2: 334–346PubMedGoogle Scholar
  151. Tenover FC (1986) Studies of antimicrobial resistance genes using DNA probes. Antimi-crob Agents Chemother 29: 721–725Google Scholar
  152. Then RL (1982) Mechanisms of resistance to trimethoprim, the sulfonamides, and trimethoprim-sulfamethoxazole. Rev Infect Dis 4: 261–269PubMedGoogle Scholar
  153. Then RL, Hermann F (1981) Mechanisms of trimethoprim resistance in enterobacteria isolated in Finland. Chemotherapy 27: 192–199PubMedGoogle Scholar
  154. Threlfall EJ, Ward LR, Rowe B (1978) Spread of multiresistant strains of Salmonella typhimurium phage types 204 and 193 in Britain. Br Med J 2: 997PubMedGoogle Scholar
  155. Threlfall EJ, Rowe B, Huq I (1980b) Plasmid-encoded multiple antibiotic resistance in Vi-brio cholerae el tor from Bangladesh. Lancet 1I: 1247–1248PubMedGoogle Scholar
  156. Threlfall EJ, Frost JA, King HC, Rowe B (1983) Plasmid-encoded trimethoprim resistance in salmonellas isolated in Britain between 1970 and 1981. J Hyg 90: 55–60Google Scholar
  157. Threlfall EJ, Ward LR, Rowe B (1986) R plasmids of Salmonella typhimurium in the United Kingdom. J Antimicrob Chemother 18 [Suppl C]: 175–177PubMedGoogle Scholar
  158. Tiemens KM, Shipley PL, Correia RA, Shields DS, Guerrant RL (1984) Sulfamethoxazole-trimethoprim-resistant Shigella flexneri in northeast Brazil. Antimicrob Agents Chemother 25: 653–654PubMedGoogle Scholar
  159. Tietze E, Prager R, Tschape H (1982) Characterization of the transposons Tn1822 (Tc) and Tn1824 ( TpSm) and the light they throw on the natural spread of resistance genes. Plasmid 8: 253–260PubMedGoogle Scholar
  160. Tietze E, Brevet J, Tschape H (1987) Relationships among the streptothricin resistance transposons Tn1825 and Tn1826 and the trimethoprim resistance transposon Tn7. Plasmid 18: 246–249PubMedGoogle Scholar
  161. Towner KJ (1981) A clinical isolate of Escherichia coli owing its trimethoprim resistance to a chromosomally-located trimethoprim transposon. J Antimicrob Chemother 7: 157–162PubMedGoogle Scholar
  162. Towner KJ (1983) Transposon-directed mutagenesis and chromosome mobilization in Acinetobacter calcoaceticus EBF65/65. Genet Res 41: 97–102PubMedGoogle Scholar
  163. Towner KJ, Pinn PA (1981) A transferable plasmid conferring only a moderate level of resistance to trimethoprim. FEMS Microbiol Lett 10: 271–272Google Scholar
  164. Towner KJ, Wise PJ (1983) Transferable resistance plasmids as a contributory cause of increasing trimethoprim resistance in general practice. J Antimicrob Chemother 11: 33–39PubMedGoogle Scholar
  165. Towner KJ, Pearson NJ, Pinn PA, O’Grady F (1980) Increasing importance of plasmidmediated trimethoprim resistance in enterobacteria: two six-month clinical surveys. Br Med J 280: 517–519PubMedGoogle Scholar
  166. Townsend DE, Ashdown N, Greed LC, Grubb WB (1984) Analysis of plasmids mediating gentamicin resistance in methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 13: 347–352PubMedGoogle Scholar
  167. Traub WH, Kleber I (1977) Selected and spontaneous variants of Serratia marcescens with combined resistance against chloramphenicol, nalidixic acid, and trimethoprim. Chemotherapy 23: 436–451PubMedGoogle Scholar
  168. Tschape H, Tietze E, Prager R, Voigt W, Wolter E, Seltmann G (1984) Plasmid-borne streptothricin resistance in gram-negative bacteria. Plasmid 12: 189–196PubMedGoogle Scholar
  169. Volz KW, Matthews DA, Alden RA, Freer ST, Hansch C, Kaufman BT, Kraut J (1982) Crystal structure of avian dihydrofolate reductase containing phenyltriazine and NADPH. J Biol Chem 257: 2528–2536PubMedGoogle Scholar
  170. Ward LR, Rowe B, Threlfall EJ (1982) Incidence of trimethoprim resistance in salmonellae isolated in Britain: a twelve year study. Lancet 11: 705–706Google Scholar
  171. Werner RG, Goeth H (1984) Trimethoprim failure to penetrate into Pseudomonas aeruginosa cells. FEMS Microbiol Lett 23: 201–204Google Scholar
  172. Wiedemann B, Meyer JF, Zuhlsdorf MT (1986) Insertions of resistance genes into Tn21like transposons. J Antimicrob Chemother 18 [Suppl C]: 85–92PubMedGoogle Scholar
  173. Wise EM, Abou-Donia MM (1975) Sulfonamide resistance mechanism in E. coli: R plasmids can determine sulfonamide-resistant dihydropteroate synthases. Proc Natl Acad Sci USA 72: 2621–2525PubMedGoogle Scholar
  174. Young HK, Amyes SGB (1983) Trimethoprim-resistance: an epidemic caused by two related transposons. In: Spitzy KH, Karrer K (eds) Proc 13th Int Congr Chemother. Egerman, Vienna, 87: 93–96Google Scholar
  175. Young HK, Amyes SGB (1985) Characterization of a new transposon-mediated trimethoprim-resistant dihydrofolate reductase. Biochem Pharmacol 34: 4334–4337PubMedGoogle Scholar
  176. Young HK, Amyes SGB ( 1986 a) A new mechanism of plasmid trimethoprim resistance. Characterization of an inducible dihydrofolate reductase. J Biol Chem 261: 2503–2505Google Scholar
  177. Young HK, Jesudason MV, Koshi G, Amyes SGB (1986) Unusual expression of new lowlevel-trimethoprim-resistance plasmids. J Clin Microbiol 24: 61–64PubMedGoogle Scholar
  178. Zaman K, Yunis MD, Baqui AH, Hossain KMB, Khan MU (1983) Cotrimoxazole-resistant Shigella dysenteriae type 1 outbreak in a family in rural Bangladesh. Lancet II:796–797Google Scholar
  179. Zolg JW, Hanggi UT (1981) Characterization of a R plasmid-associated, trimethoprim-resistant dihydrofolate reductase and determination of the nucleotide sequence of the reductase gene. Nucleic Acids Res 9: 697–710PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1989

Authors and Affiliations

  • L. P. Elwell
  • M. E. Fling

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