1887

Microbiology

Volume 150, Issue 5

Inability of organisms to incorporate bromodeoxyuridine suggests the absence of a salvage pathway for thymidine Free

Abstract

Because thymidine metabolism is a potential target for therapy of pneumonia, it was investigated whether organisms have a salvage pathway for thymidine by administering 5-bromo-2′-deoxyuridine (BrdU) to mice and rats with pneumonia. Although BrdU incorporation was detected in host cells, no incorporation was seen in organisms infecting either rats or mice. This suggests that organisms do not have a salvage pathway for thymidine, and that inhibitors of synthesis, such as thymidylate synthase inhibitors, may be effective drugs for treating pneumonia.

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Keyword(s): BrdU, 5-bromo-2′-deoxyuridine and PCP, Pneumocystis pneumonia
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2004-05-01
2020-04-02
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References

  1. Anderson A. C., Perry K. M., Freymann D. M., Stroud R. M.. 2000; The crystal structure of thymidylate synthase from Pneumocystis carinii reveals a fungal insert important for drug design. J Mol Biol297:645–657[CrossRef]
     [Google Scholar]
  2. Angus C. W., Tu A., Vogel P., Qin M., Kovacs J. A.. 1996; Expression of variants of the major surface glycoprotein of Pneumocystis carinii. J Exp Med183:1229–1234[CrossRef]
     [Google Scholar]
  3. Danenberg P. V., Malli H., Swenson S.. 1999; Thymidylate synthase inhibitors. Semin Oncol26:621–631
     [Google Scholar]
  4. Dolbeare F.. 1995a; Bromodeoxyuridine: a diagnostic tool in biology and medicine, part II: oncology, chemotherapy and carcinogenesis. Histochem J27:923–964[CrossRef]
     [Google Scholar]
  5. Dolbeare F.. 1995b; Bromodeoxyuridine: a diagnostic tool in biology and medicine, part I: historical perspectives, histochemical methods and cell kinetics. Histochem J27:339–369[CrossRef]
     [Google Scholar]
  6. Dolbeare F.. 1996; Bromodeoxyuridine: a diagnostic tool in biology and medicine, part III. Proliferation in normal, injured and diseased tissue, growth factors, differentiation, DNA replication sites and in situ hybridization. Histochem J28:531–575[CrossRef]
     [Google Scholar]
  7. Edman J. C., Kovacs J. A., Masur H., Santi D. V., Elwood H. J., Sogin M. L.. 1988; Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi. Nature334:519–522[CrossRef]
     [Google Scholar]
  8. Edman U., Edman J. C., Lundgren B., Santi D. V.. 1989; Isolation and expression of the Pneumocystis carinii thymidylate synthase gene. Proc Natl Acad Sci U S A86:6503–6507[CrossRef]
     [Google Scholar]
  9. Flynn K. J., Riberdy J. M., Christensen J. P., Altman J. D., Doherty P. C.. 1999; In vivo proliferation of naive and memory influenza-specific CD8+ T cells. Proc Natl Acad Sci U S A96:8597–8602[CrossRef]
     [Google Scholar]
  10. Gutierrez J. C., Callejas S., Borniquel S., Martin-Gonzalez A.. 2000; DNA methylation in ciliates: implications in differentiation processes. Int Microbiol3:139–146
     [Google Scholar]
  11. Helweg-Larsen J., Benfield T. L., Eugen-Olsen J., Lundgren J. D., Lundgren B.. 1999; Effects of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associatedP. carinii pneumonia. Lancet354:1347–1351[CrossRef]
     [Google Scholar]
  12. Hodson J. A., Bailis J. M., Forsburg S. L.. 2003; Efficient labeling of fission yeast Schizosaccharomyces pombe with thymidine and BUdR. Nucleic Acids Res31:e134[CrossRef]
     [Google Scholar]
  13. Hughes W. T.. 1998; Use of dapsone in the prevention and treatment of Pneumocystis carinii pneumonia: a review. Clin Infect Dis27:191–204[CrossRef]
     [Google Scholar]
  14. Hughes W., Leoung G., Kramer F..14 other authors 1993; Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med328:1521–1527[CrossRef]
     [Google Scholar]
  15. Jarroll E. L., Manning P., Berrada A., Hare D., Lindmark D. G.. 1989; Biochemistry and metabolism of Giardia. J Protozool36:190–197[CrossRef]
     [Google Scholar]
  16. Jiang L., Lee P. C., White J., Rathod P. K.. 2000; Potent and selective activity of a combination of thymidine and 1843U89, a folate-based thymidylate synthase inhibitor, against Plasmodium falciparum. Antimicrob Agents Chemother44:1047–1050[CrossRef]
     [Google Scholar]
  17. Kazanjian P., Armstrong W., Hossler P. A., Burman W., Richardson J., Lee C. H., Crane L., Katz J., Meshnick S. R.. 2000; Pneumocystis carinii mutations are associated with duration of sulfa or sulfone prophylaxis exposure in AIDS patients. J Infect Dis182:551–557[CrossRef]
     [Google Scholar]
  18. Kellett M., Potten C. S., Rew D. A.. 1992; A comparison of in vivo cell proliferation measurements in the intestine of mouse and man. Epithelial Cell Biol1:147–155
     [Google Scholar]
  19. Kovacs J. A., Masur H.. 2000; Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med342:1416–1429[CrossRef]
     [Google Scholar]
  20. Kovacs J. A., Halpern J. L., Swan J. C., Moss J., Parrillo J. E., Masur H.. 1988; Identification of antigens and antibodies specific for Pneumocystis carinii. J Immunol140:2023–2031
     [Google Scholar]
  21. Kovacs J. A., Allegra C. J., Masur H.. 1990; Characterization of dihydrofolate reductase of Pneumocystis carinii and Toxoplasma gondii. Exp Parasitol71:60–68[CrossRef]
     [Google Scholar]
  22. Kovacs J. A., Gill V. J., Meshnick S., Masur H.. 2001a; New insights into transmission, diagnosis, and drug treatment of Pneumocystis carinii pneumonia. JAMA (J Am Med Assoc)286:2450–2460[CrossRef]
     [Google Scholar]
  23. Kovacs J. A., Lempicki R. A., Sidorov I. A..17 other authors 2001b; Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med194:1731–1741[CrossRef]
     [Google Scholar]
  24. Ma L., Borio L., Masur H., Kovacs J. A.. 1999; Pneumocystis carinii dihydropteroate synthase but not dihydrofolate reductase gene mutations correlate with prior trimethoprim-sulfamethoxazole or dapsone use. J Infect Dis180:1969–1978[CrossRef]
     [Google Scholar]
  25. Martinez A., Kovacs J. A.. 1993; Development and characterization of a rapid screening assay for identifying antipneumocystis agents. Antimicrob Agents Chemother37:1674–1678[CrossRef]
     [Google Scholar]
  26. Mei Q., Wang Q., Chen Y., Liu Y., Fan W., Li P.. 1995; Experimental and clinical study on pneumocystosis. IV. Use of a 4D7 monoclonal antibody to detect Pneumocystis carinii by immunoperoxidase staining. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi13:130–133 in Chinese
     [Google Scholar]
  27. Navin T. R., Beard C. B., Huang L..7 other authors 2001; Effect of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of P. carinii pneumonia in patients with HIV-1: a prospective study. Lancet358:545–549[CrossRef]
     [Google Scholar]
  28. Phair J., Munoz A., Detels R., Kaslow R., Rinaldo C., Saah A.. 1990; The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. Multicenter AIDS Cohort Study Group. N Engl J Med322:161–165[CrossRef]
     [Google Scholar]
  29. Roblot F., Godet C., Le Moal G..9 other authors 2002; Analysis of underlying diseases and prognosis factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients. Eur J Clin Microbiol Infect Dis21:523–531[CrossRef]
     [Google Scholar]
  30. Santi D. V., Edman U., Minkin S., Greene P. J.. 1991; Purification and characterization of recombinant Pneumocystis carinii thymidylate synthase. Protein Expr Purif2:350–354[CrossRef]
     [Google Scholar]
  31. Sattler F. R., Cowan R., Nielsen D. M., Ruskin J.. 1988; Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective, noncrossover study. Ann Intern Med109:280–287[CrossRef]
     [Google Scholar]
  32. Sherman I. W.. 1979; Biochemistry of Plasmodium (malarial parasites. Microbiol Rev43:453–495
     [Google Scholar]
  33. Vasconcelles M. J., Bernardo M. V., King C., Weller E. A., Antin J. H.. 2000; Aerosolized pentamidine as pneumocystis prophylaxis after bone marrow transplantation is inferior to other regimens and is associated with decreased survival and an increased risk of other infections. Biol Blood Marrow Transplant6:35–43[CrossRef]
     [Google Scholar]
  34. Vernis L., Piskur J., Diffley J. F.. 2003; Reconstitution of an efficient thymidine salvage pathway in Saccharomyces cerevisiae. Nucleic Acids Res31:e120[CrossRef]
     [Google Scholar]
  35. Walzer P. D., Runck J., Steele P., White M., Linke M. J., Sidman C. L.. 1997; Immunodeficient and immunosuppressed mice as models to test anti-Pneumocystis carinii drugs. Antimicrob Agents Chemother41:251–258
     [Google Scholar]
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Inability of Pneumocystis organisms to incorporate bromodeoxyuridine suggests the absence of a salvage pathway for thymidine
Microbiology 150, 1179 (2004); https://doi.org/10.1099/mic.0.26890-0
/content/journal/micro/10.1099/mic.0.26890-0
/content/journal/micro/10.1099/mic.0.26890-0
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