Skip to main content

Advertisement

Log in

Group I intron renders differential susceptibility of Candida albicans to Bleomycin

  • Original Paper
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

The alarming increase in drug resistance gained by fungal pathogens has raised an urgent need to develop drugs against novel targets. Candida albicans, an opportunistic fungal pathogen, harbors in its 25S rRNA gene, a self-splicing Group I intron, which can act as a selective drug target. We report that Bleomycin selectively inhibits the self-splicing of Group I intron of C. albicans at IC50 = 1.2 μM, leading to accumulation of precursor RNA as evinced by Reverse Transcriptase PCR. Drug susceptibility assays including MIC determination, growth curve analysis and disc diffusion assays indicate a strong susceptibility of the intron-containing strain (4-1) than the intronless strain (62-1). These results on the preferential targeting of Group I intron of C. albicans by Bleomycin might form a basis for design of small molecules that inhibit self-splicing of RNA as a antimicrobial tool against life-threatening microorganisms.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Berry DE, Chang LH, Hecht SM (1985) DNA damage and growth inhibition in cultured human cells by bleomycin congeners. Biochemistry 24:3207–3214

    Article  PubMed  CAS  Google Scholar 

  • Boucher HS, Mercure S, Montplaisir S, Lemay G (1996) A novel group I intron in Candida dubliniensis is homologous to a Candida albicans intron. Gene 180:189–196

    Article  PubMed  CAS  Google Scholar 

  • Carter BJ, De Vroom E, Long CE, Van der Marel G, Van Boom JH., Hecht SM (1990) Site-specific cleavage of RNA by Fe(II) bleomycin. Proc Natl Acad Sci USA 87:9373–9377

    Article  PubMed  CAS  Google Scholar 

  • D’ Andrea AD, Haseltine WA (1978) Modification of DNA by Aflatoxin B1 creates alkali-labile lesions in DNA at positions of guanine and adenine. Proc Natl Acad Sci USA 75:3608–3612

    Article  PubMed  Google Scholar 

  • Disney MD, Childs JL, Turner DH (2004) New approaches to targeting RNA with oligonucleotides: Inhibition of group I intron self-splicing. Biopolymers 73:151–161

    Article  PubMed  CAS  Google Scholar 

  • Embley TM, Dyal P, Kilvington S (1992) A group I intron in the small subunit ribosomal RNA gene from Naegleria andersoni ssp. andersoni strain PPMF-6. Nucleic Acids Res 20:6411

    Article  PubMed  CAS  Google Scholar 

  • Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC (1998) Potent and specific genetic interference by double stranded RNA in Caenorhabditis elegans. Nature 391:806–811

    Article  PubMed  CAS  Google Scholar 

  • Gast RJ, Fuerst PA, Byers TJ (1994) Discovery of group I introns in the nuclear small subunit ribosomal RNA genes of Acanthamoeba. Nucleic Acids Res 22:592–596

    Article  PubMed  CAS  Google Scholar 

  • Graybill JR, Bocanegra R, Fothergill A, Rinaldi MG (1996) Bleomycin therapy of experimental disseminated candidiasis in mice. Antimicrob Agents Chemother 40:816–818

    PubMed  CAS  Google Scholar 

  • Haidle CW, Bearden J Jr (1975) Effect of bleomycin on an RNA–DNA hybrid. Biochem Biophys Res Commun 65:815–821

    Article  PubMed  CAS  Google Scholar 

  • Hecht SM (1986) The chemistry of activated bleomycin. Acc Chem Res 19:383–391

    Article  CAS  Google Scholar 

  • Krishnamoorthy CR, Vanderwall DE, Kozarich JW, Stubbe J (1988) Chemistry of bleomycin attack on DNA–RNA hybrids and DNAs. J Am Chem Soc 110:2008–2009

    Article  CAS  Google Scholar 

  • Liu Y, Leibowitz MJ (1993) Variation and in vitro splicing of group I introns in rRNA genes of Pneumocystis carinii. Nucleic Acids Res 21:2415–2421

    Article  PubMed  CAS  Google Scholar 

  • Mehta R, Champney WS (2002) 30S ribosomal subunit assembly is a target for inhibition by aminoglycosides in Escherichia coli. Antimicrob Chemother 46:1546–1549

    Article  CAS  Google Scholar 

  • Mercure S, Cousineau L, Montplaisir S, Belhumeur P, Lemay G. (1997) Expression of a reporter gene interrupted by the Candida albicans group I intron is inhibited by base analogs. Nucleic Acids Res 25:431–437

    Article  PubMed  CAS  Google Scholar 

  • Mercure S, Montplaisir S, Lemay G (1993) Correlation between the presence of a self-splicing intron in the 25S rDNA of C. albicans and strains susceptibility to 5-fluorocytosine. Nucleic Acids Res 21:6020–6027

    Article  PubMed  CAS  Google Scholar 

  • Miletti KE, Leibowitz MJ (2000) Pentamidine inhibition of group I intron splicing in Candida albicans correlates with growth inhibition. Antimicrob Agents Chemother 44:958–966

    Article  PubMed  CAS  Google Scholar 

  • Moazed D, Noller HF (1987) Interaction of antibiotics with functional sites in 16S ribosomal RNA. Nature 327:389–394

    Article  PubMed  CAS  Google Scholar 

  • Ogle JM, Brodersen DE, Clemons WM Jr, Tarry MJ, Carter AP, Ramakrishnan V (2001) Recognition of cognate transfer RNA by the 30S ribosomal subunit. Science 292:897–902

    Article  PubMed  CAS  Google Scholar 

  • Pearson ND, Prescott CD (1997) RNA as a drug target. Chem Biol 4:409–414

    Article  PubMed  CAS  Google Scholar 

  • Sogin ML, Edman JC (1989) A self-splicing intron in the small subunit rRNA gene of Pneumocystis carinii. Nucleic Acids Res 17:5349–5359

    Article  PubMed  CAS  Google Scholar 

  • Sternberg S (1994) The emerging fungal threat. Science 266:1632–1634

    Article  PubMed  CAS  Google Scholar 

  • Stubbe J, Kozarich JW (1987) Mechanism of bleomycin induced DNA degradation. Chem Rev 87:1107–1136

    Article  CAS  Google Scholar 

  • Takeshita M, Grollman AP, Ohtsubo E., Ohtsubo H (1978) Interaction of Bleomycin with DNA. Proc Natl Acad Sci USA 75:5983–5987

    Article  PubMed  CAS  Google Scholar 

  • Vicens Q, Westhof E (2001) Crystal structure of paromomycin docked into the eubacterial ribosomal decoding A site. Structure (Cambridge) 9:647–658

    Article  CAS  Google Scholar 

  • Von Ahsen U, Davies J, Schroeder R (1991) Antibiotic inhibition of group I ribozyme function. Nature 368:368–370

    Article  Google Scholar 

  • Von Ahsen U, Davies J, Schroeder R (1992) Non-competitive inhibition of a group I intron RNA self-splicing by aminoglycoside antibiotics. J Mol Biol 226:935–941

    Article  Google Scholar 

  • Von Ahsen U, Schroeder R (1991) Streptomycin inhibits splicing of group I introns by competition with the guanosine substrate. Nucleic Acids Res 19:2261–2265

    Article  Google Scholar 

  • Vormann J (2003) Magnesium: nutrition and metabolism. J Mol Aspects Med 24:27–37

    Article  CAS  Google Scholar 

  • Wank H, Rogers J, Davies J, Schroeder R (1994) Peptide antibiotics of the tuberactinomycin family as inhibitors of group I intron RNA splicing. J Mol Biol 236:1001–1010

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

We sincerely thank Dr. G. Jayaraman, Dept. of Genetics, University of Madras for his valuable suggestions and for providing gel documentation facilities.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Malathi Raghunathan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jayaguru, P., Raghunathan, M. Group I intron renders differential susceptibility of Candida albicans to Bleomycin. Mol Biol Rep 34, 11–17 (2007). https://doi.org/10.1007/s11033-006-9002-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-006-9002-1

Keywords

Navigation