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The Multidrug Transporters Belonging to Major Facilitator Superfamily (MFS) in Mycobacterium tuberculosis

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Abstract

Background

Both intrinsic and acquired multidrug resistance play an important role in the insurgence of tuberculosis. Detailed knowledge of the molecular basis of drug recognition and transport by multidrug transport systems is required for the development of new antibiotics that are not extruded or of inhibitors that block the multidrug transporter and allow traditional antibiotics to be effective.

Materials and Methods

We have undertaken the inventory of the drug transporters subfamily, included in the major facilitator superfamily (MFS), encoded by the complete genome of Mycobacterium tuberculosis (MTB). These proteins were identified on the basis of their characteristic stretches of amino acids and transmembrane segments (TMS) number.

Conclusions

Genome analysis and searches of homology between the identified transporters and proteins characterized in other organisms revealed 16 open reading frames encoding putative drug efflux pumps belonging to MFS. In the case of two of them, we also have demonstrated that they function as drug efflux proteins.

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References

  1. Draper P. (1998) The outer parts of the mycobacterial envelope as permeability barriers. Front. Biosci. 15: 1253–1261.

    Article  Google Scholar 

  2. Nikaido H. (2001) Preventing drug access to targets: cell surface permeability barriers and active efflux in bacteria. Cell Dev. Biol. 12: 215–223.

    Article  CAS  Google Scholar 

  3. Kohler T, Pechere JC, Plesiat P. (1999) Bacterial efflux systems of medical importance. Cell Mol. Life Sci. 56: 771–778.

    Article  CAS  PubMed  Google Scholar 

  4. Saier Jr MH. (2000) A functional-phylogenetic classification system for transmembrane solute transporters. Microbiol. Mol. Biol. Rev. 64: 354–411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Takiff HT, Cimino M, Musso MC, et al. (1996) Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance in Mycobacterium smegmatis. Proc. Natl. Acad. Sci. U.S.A. 93: 362–366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. De Rossi E, Blokpoel MC, Cantoni R, et al. (1998) Molecular cloning and functional analysis of a novel tetracycline resistance determinant, tet(V), from Mycobacterium smegmatis. Antimicrob. Agents Chemother. 42: 1931–1937.

    PubMed  PubMed Central  Google Scholar 

  7. Aínsa JA, Blokpoel MC, Otal I, et al. (1998) Molecular cloning and characterization of Tap, a putative multidrug efflux pump present in Mycobacterium fortuitum and Mycobacterium tuberculosis. J. Bacteriol. 180: 5836–5843.

    PubMed  PubMed Central  Google Scholar 

  8. Silva PE, Bigi F, de La Paz Santangelo M, et al. (2001) Characterization of P55, a multidrug efflux pump in Mycobacterium bovis and Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 45: 800–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Doran JL, Pang Y, Mdluli KE, et al. (1997) Mycobacterium tuberculosis efpA encodes an efflux protein of the QacA transporter family. Clin. Diagn. Lab. Immunol. 4: 23–32.

    PubMed  PubMed Central  CAS  Google Scholar 

  10. De Rossi E, Branzoni M, Cantoni R, et al. (1998) mmr, a Mycobacterium tuberculosis gene conferring resistance to small cationic dyes and inhibitors. J. Bacteriol. 180: 6068–6071.

    PubMed  PubMed Central  Google Scholar 

  11. Banerjee SK, Bhatt K, Misra P, et al. (2000) Involvement of a natural transport system in the process of efflux-mediated drug resistance in Mycobacterium smegmatis. Mol. Gen. Genet. 262: 949–956.

    Article  CAS  PubMed  Google Scholar 

  12. Braibant M, Gilot P, Content J. (2000) The ATP binding cassette (ABC) transport systems of Mycobacterium tuberculosis. FEMS Microbiol. Rev. 24: 449–467.

    Article  CAS  PubMed  Google Scholar 

  13. Pao SS, Paulsen IT, Saier Jr MH. (1998) Major Facilitator Superfamily. Microbiol. Mol. Biol. Rev. 62: 1–34.

    PubMed  PubMed Central  CAS  Google Scholar 

  14. Saier Jr MH, Paulsen IT. (2001) Phylogeny of multidrug transporters. Semin. Cell Dev. Biol. 12: 205–213.

    Article  CAS  PubMed  Google Scholar 

  15. Saier Jr MH, Beatty JT, Goffeau A, et al. (1999) The major facilitator superfamily. J. Mol. Microbiol. Biotechnol. 1: 257–279.

    PubMed  CAS  Google Scholar 

  16. Paulsen IT, Brown MH, Skurray RA. (1996) Proton-dependent multidrug efflux systems. Microbiol. Rev. 60: 575–608.

    PubMed  PubMed Central  CAS  Google Scholar 

  17. Varela MF, Sansom CE, Griffith JK. (1995) Mutational analysis and molecular modelling of an amino acid sequence motif conserved in antiporters but not symporters in a transporter superfamily. Mol. Membr. Biol. 12: 313–319.

    Article  CAS  PubMed  Google Scholar 

  18. Cole ST, Brosch R, Parkhill J, et al. (1998) Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393: 537–544.

    Article  CAS  PubMed  Google Scholar 

  19. Bailey TL, Gribskov M. (1998) Combining evidence using p-values: application to sequence homology searches. Bioinformatics 14: 48–54.

    Article  CAS  PubMed  Google Scholar 

  20. Thompson JD, Higgins DG, Gibson TJ. (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22: 4673–4680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Page RDM. (1996) TreeView: an application to display phylogenetic trees on personal computers. Comput. Appl. Biosci. 12: 357–358.

    PubMed  CAS  Google Scholar 

  22. Altschul M, Madden TL, Schaffer AA, et al. (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25: 3389–3402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sonnhammer ELL, von Heijne G, Krogh A. (1998) A hidden Markov model for predicting transmembrane helices in protein sequences. In Glasgow J, Littlejohn T, Major F, Lathrop R, Sankoff D, Sensen C, eds. Proceedings of the Sixth International Conference on Intelligent Systems for Molecular Biology. Menlo Park, CA: AAAI Press; pp. 175–182.

    Google Scholar 

  24. Donnelly-Wu MK, Jacobs Jr R, Hatfull GF. (1993) Superinfection immunity of mycobacteriophage L5: applications for genetic transformation of mycobacteria. Mol. Microbiol. 7: 407–17.

    Article  CAS  PubMed  Google Scholar 

  25. Aínsa JA, Martín C, Cabeza M, et al. (1996) Costruction of a family of Mycobacterium/Escherichia coli shuttle vectors derived from pAL5000 and pACYC184: their use for cloning an antibiotic-resistance gene from Mycobacterium fortuitum. Gene 176: 23–26.

    Article  PubMed  Google Scholar 

  26. Mortimer PGS, Piddock LJV. (1991) A comparison of methods used for measuring the accumulation of quinolones by Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. J. Antimicrob. Chemother. 28: 639–653.

    Article  CAS  PubMed  Google Scholar 

  27. Williams KJ, Chung GA, Piddock LJ. (1998) Accumulation of norfloxacin by Mycobacterium aurum and Mycobacterium smegmatis. Antimicrob. Agents Chemother. 42: 795–800.

    PubMed  CAS  Google Scholar 

  28. Sander P, De Rossi E, Boddinghaus B, et al. (2000) Contribution of the multidrug efflux pump LfrA to innate mycobacterial drug resistance. FEMS Microbiol. Lett. 193: 19–23.

    Article  CAS  PubMed  Google Scholar 

  29. Bush K, Goldschmidt R. (2000) Effectiveness of fluoroquinolones against gram-positive bacteria. Curr. Opin. Investig. Drugs 1: 22–30.

    PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by MURST-COFIN-1998 and by the European Union research project “Quality of Life and Management of Living Resources” (Contract N° QLK2-CT-2000-01761) and by Fondo d′Ateneó per la Ricerca 2002 (F.A.R.). J.A.A. is a recipient of a “Programa Ramon y Cajal” research fellowship (Spanish Ministry of Science and Technology). P.E.A.S. was supported by CAPES (Brazilian Ministry of Education).

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Author notes

  1. Pedro E. A. Silva

    Present address: Fundaçaõ Universidade Federal do Rio Grande de Rio Grande, Rio Grande, Brasil

Authors and Affiliations

  1. Dipartimento di Genetica e Microbiologia, Università degli Studi di Pavia, via Ferrata 1, 27100, Pavia, Italy

    Edda De Rossi & Marco Bellinzoni

  2. Istituto Circuiti Elettronici, CNR, Genova, Italy

    Patrizio Arrigo

  3. Departamento de Microbiologia Medicina Preventiva y Salud Pública, Universidad de Zaragoza, Zaragoza, Spain

    Pedro E. A. Silva, Carlos Martin & José A. Aínsa

  4. Dipartimento di Biologia Sperimentale Ambientale ed Applicata, Università degli Studi di Genova, Genova, Italy

    Paola Guglierame & Giovanna Riccardi

Authors
  1. Edda De Rossi
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  2. Patrizio Arrigo
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  3. Marco Bellinzoni
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  4. Pedro E. A. Silva
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  6. José A. Aínsa
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Correspondence to Edda De Rossi.

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De Rossi, E., Arrigo, P., Bellinzoni, M. et al. The Multidrug Transporters Belonging to Major Facilitator Superfamily (MFS) in Mycobacterium tuberculosis. Mol Med 8, 714–724 (2002). https://doi.org/10.1007/BF03402035

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