1887

Abstract

In order to gain additional understanding of the physiological mechanisms used by bacteria to maintain surface homeostasis and to identify potential targets for new antibacterial drugs, we analysed the variation of the transcriptional profile in response to inhibitory and subinhibitory concentrations of vancomycin. Our analysis identified 153 genes differentially regulated after exposing bacteria to a concentration of the drug ten times higher than the MIC, and 141 genes differentially expressed when bacteria were growing in a concentration of the drug eightfold lower than the MIC. Hierarchical clustering analysis indicated that the response to these different conditions is different, although with some overlap. This approach allowed us to identify several genes whose products could be involved in the protection from antibiotic stress targeting the envelope and help to confer the basal level of resistance to antibacterial drugs, such as Rv2623 (UspA-like), Rv0116c, PE20-PPE31, PspA and proteins related to toxin–antitoxin systems. Moreover, we also demonstrated that the alternative sigma factor confers basal resistance to vancomycin, once again underlining its importance in the physiology of the mycobacterial surface stress response.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.024802-0
2009-04-01
2020-08-14
Loading full text...

Full text loading...

/deliver/fulltext/micro/155/4/1093.html?itemId=/content/journal/micro/10.1099/mic.0.024802-0&mimeType=html&fmt=ahah

References

  1. Arcus V. L., Rainey P. B., Turner S. J.. 2005; The PIN-domain toxin-antitoxin array in mycobacteria. Trends Microbiol13:360–365
    [Google Scholar]
  2. Azad A. K., Sirakova T. D., Fernandes N. D., Kolattukudy P. E.. 1997; Gene knockout reveals a novel gene cluster for the synthesis of a class of cell wall lipids unique to pathogenic mycobacteria. J Biol Chem272:16741–16745
    [Google Scholar]
  3. Bacon J., James B. W., Wernisch L., Williams A., Morley K. A., Hatch G. J., Mangan J. A., Hinds J., Stoker N. G.. other authors 2004; The influence of reduced oxygen availability on pathogenicity and gene expression in Mycobacterium tuberculosis . Tuberculosis (Edinb84:205–217
    [Google Scholar]
  4. Barry C. E. III. 2001; Interpreting cell wall ‘virulence factors' of Mycobacterium tuberculosis . Trends Microbiol9:237–241
    [Google Scholar]
  5. Betts J. C., Lukey P. T., Robb L. C., McAdam R. A., Duncan K.. 2002; Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol43:717–731
    [Google Scholar]
  6. Boshoff H. I., Barry C. E. III. 2005; Tuberculosis – metabolism and respiration in the absence of growth. Nat Rev Microbiol3:70–80
    [Google Scholar]
  7. Boshoff H. I., Myers T. G., Copp B. R., McNeil M. R., Wilson M. A., Barry C. E. III. 2004; The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. J Biol Chem279:40174–40184
    [Google Scholar]
  8. Cao M., Wang T., Ye R., Helmann J. D.. 2002; Antibiotics that inhibit cell wall biosynthesis induce expression of the Bacillus subtilis SigW and SigM regulons. Mol Microbiol45:1267–1276
    [Google Scholar]
  9. Clegg S. J., Jia W., Cole J. A.. 2006; Role of the Escherichia coli nitrate transport protein, NarU, in survival during severe nutrient starvation and slow growth. Microbiology152:2091–2100
    [Google Scholar]
  10. Cole S. T., Brosch R., Parkhill J., Garnier T., Churcher C., Harris D., Gordon S. V., Eiglmeier K., Gas S.. other authors 1998; Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature393:537–544
    [Google Scholar]
  11. Danilchanka O., Mailaender C., Niederweis M.. 2008; Identification of a novel multidrug efflux pump of Mycobacterium tuberculosis . Antimicrob Agents Chemother52:2503–2511
    [Google Scholar]
  12. Darwin A. J.. 2005; The phage-shock-protein response. Mol Microbiol57:621–628
    [Google Scholar]
  13. Darwin K. H., Lin G., Chen Z., Li H., Nathan C. F.. 2005; Characterization of a Mycobacterium tuberculosis proteasomal ATPase homologue. Mol Microbiol55:561–571
    [Google Scholar]
  14. Desjardin L. E., Hayes L. G., Sohaskey C. D., Wayne L. G., Eisenach K. D.. 2001; Microaerophilic induction of the alpha-crystallin chaperone protein homologue ( hspX ) mRNA of Mycobacterium tuberculosis . J Bacteriol183:5311–5316
    [Google Scholar]
  15. Dougan D. A., Mogk A., Bukau B.. 2002; Protein folding and degradation in bacteria: to degrade or not to degrade? That is the question. Cell Mol Life Sci59:1607–1616
    [Google Scholar]
  16. Downing K. J., Mischenko V. V., Shleeva M. O., Young D. I., Young M., Kaprelyants A. S., Apt A. S., Mizrahi V.. 2005; Mutants of Mycobacterium tuberculosis lacking three of the five rpf -like genes are defective for growth in vivo and for resuscitation in vitro . Infect Immun73:3038–3043
    [Google Scholar]
  17. Dye C., Scheele S., Dolin P., Pathania V., Raviglione M. C.. 1999; Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA282:677–686
    [Google Scholar]
  18. Fisher M. A., Plikaytis B. B., Shinnick T. M.. 2002; Microarray analysis of the Mycobacterium tuberculosis transcriptional response to the acidic conditions found in phagosomes. J Bacteriol184:4025–4032
    [Google Scholar]
  19. Florczyk M. A., McCue L. A., Stack R. F., Hauer C. R., McDonough K. A.. 2001; Identification and characterization of mycobacterial proteins differentially expressed under standing and shaking culture conditions, including Rv2623 from a novel class of putative ATP-binding proteins. Infect Immun69:5777–5785
    [Google Scholar]
  20. Gandhi N. R., Moll A., Sturm A. W., Pawinski R., Govender T., Lalloo U., Zeller K., Andrews J., Friedland G.. 2006; Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet368:1575–1580
    [Google Scholar]
  21. Geiman D. E., Kaushal D., Ko C., Tyagi S., Manabe Y. C., Schroeder B. G., Fleischmann R. D., Morrison N. E., Converse P. J.. other authors 2004; Attenuation of late-stage disease in mice infected by the Mycobacterium tuberculosis mutant lacking the SigF alternate sigma factor and identification of SigF-dependent genes by microarray analysis. Infect Immun72:1733–1745
    [Google Scholar]
  22. Geiman D. E., Raghunand T. R., Agarwal N., Bishai W. R.. 2006; Differential gene expression in response to exposure to antimycobacterial agents and other stress conditions among seven Mycobacterium tuberculosis whiB -like genes. Antimicrob Agents Chemother50:2836–2841
    [Google Scholar]
  23. Gerdes K., Rasmussen P. B., Molin S.. 1986; Unique type of plasmid maintenance function: postsegregational killing of plasmid-free cells. Proc Natl Acad Sci U S A83:3116–3120
    [Google Scholar]
  24. Gey van Pittius N. C., Sampson S. L., Lee H., Kim Y., van Helden P. D., Warren R. M.. 2006; Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 ( esx ) gene cluster regions. BMC Evol Biol6:95
    [Google Scholar]
  25. Hampshire T., Soneji S., Bacon J., James B. W., Hinds J., Laing K., Stabler R. A., Marsh P. D., Butcher P. D.. 2004; Stationary phase gene expression of Mycobacterium tuberculosis following a progressive nutrient depletion: a model for persistent organisms?. Tuberculosis (Edinb84:228–238
    [Google Scholar]
  26. Hayes F.. 2003; Toxins-antitoxins: plasmid maintenance, programmed cell death, and cell cycle arrest. Science301:1496–1499
    [Google Scholar]
  27. Hoffmann C., Leis A., Niederweis M., Plitzko J. M., Engelhardt H.. 2008; Disclosure of the mycobacterial outer membrane: cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proc Natl Acad Sci U S A105:3963–3967
    [Google Scholar]
  28. Jacobs W. R. Jr, Kalpana G. V., Cirillo J. D., Pascopella L., Snapper S. B., Udani R. A., Jones W., Barletta R. G., Bloom B. R.. 1991; Genetic systems for mycobacteria. Methods Enzymol204:537–555
    [Google Scholar]
  29. Jaffe A., Ogura T., Hiraga S.. 1985; Effects of the ccd function of the F plasmid on bacterial growth. J Bacteriol163:841–849
    [Google Scholar]
  30. Jain M. J., Chow E. D., Cox J.. 2008; The MmpL proteins. In The Mycobacterial Cell Envelope pp201–210 Edited by Daffé M., Reyrat J. M.. Washington, DC: American Society for Microbiology;
  31. Kobayashi R., Suzuki T., Yoshida M.. 2007; Escherichia coli phage-shock protein A (PspA) binds to membrane phospholipids and repairs proton leakage of the damaged membranes. Mol Microbiol66:100–109
    [Google Scholar]
  32. Kvint K., Nachin L., Diez A., Nystrom T.. 2003; The bacterial universal stress protein: function and regulation. Curr Opin Microbiol6:140–145
    [Google Scholar]
  33. Maciag A., Dainese E., Rodriguez G. M., Milano A., Provvedi R., Pasca M. R., Smith I., Palù G., Riccardi G., Manganelli R.. 2007; Global analysis of the Mycobacterium tuberculosis Zur (FurB) regulon. J Bacteriol189:730–740
    [Google Scholar]
  34. Magnuson R. D.. 2007; Hypothetical functions of toxin-antitoxin systems. J Bacteriol189:6089–6092
    [Google Scholar]
  35. Manganelli R., Dubnau E., Tyagi S., Kramer F. R., Smith I.. 1999; Differential expression of 10 sigma factor genes in Mycobacterium tuberculosis . Mol Microbiol31:715–724
    [Google Scholar]
  36. Manganelli R., Voskuil M. I., Schoolnik G. K., Smith I.. 2001; The Mycobacterium tuberculosis ECF sigma factor SigE: role in global gene expression and survival in macrophages. Mol Microbiol41:423–437
    [Google Scholar]
  37. Manganelli R., Voskuil M. I., Schoolnik G. K., Dubnau E., Gomez M., Smith I.. 2002; Role of the extracytoplasmic-function sigma factor SigH in Mycobacterium tuberculosis global gene expression. Mol Microbiol45:365–374
    [Google Scholar]
  38. Mascher T., Margulis N. G., Wang T., Ye R. W., Helmann J. D.. 2003; Cell wall stress responses in Bacillus subtilis : the regulatory network of the bacitracin stimulon. Mol Microbiol50:1591–1604
    [Google Scholar]
  39. Milano A., Pasca M. R., Provvedi R., Lucarelli A. P., Manina G., de Jesus Lopes Ribeiro A. L., Manganelli R., Riccardi G.. 2009; Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5-MmpL5 efflux system. Tuberculosis (Edinb89:84–90
    [Google Scholar]
  40. Muttucumaru D. G., Roberts G., Hinds J., Stabler R. A., Parish T.. 2004; Gene expression profile of Mycobacterium tuberculosis in a non-replicating state. Tuberculosis (Edinb84:239–246
    [Google Scholar]
  41. Newell K. V., Thomas D. P., Brekasis D., Paget M. S.. 2006; The RNA polymerase-binding protein RbpA confers basal levels of rifampicin resistance on Streptomyces coelicolor . Mol Microbiol60:687–696
    [Google Scholar]
  42. Ohno H., Zhu G., Mohan V. P., Chu D., Kohno S., Jacobs W. R. Jr, Chan J.. 2003; The effects of reactive nitrogen intermediates on gene expression in Mycobacterium tuberculosis . Cell Microbiol5:637–648
    [Google Scholar]
  43. O'Toole R., Williams H. D.. 2003; Universal stress proteins and Mycobacterium tuberculosis . Res Microbiol154:387–392
    [Google Scholar]
  44. Paget M. S., Bae J. B., Hahn M. Y., Li W., Kleanthous C., Roe J. H., Buttner M. J.. 2001a; Mutational analysis of RsrA, a zinc-binding anti-sigma factor with a thiol-disulphide redox switch. Mol Microbiol39:1036–1047
    [Google Scholar]
  45. Paget M. S., Molle V., Cohen G., Aharonowitz Y., Buttner M. J.. 2001b; Defining the disulphide stress response in Streptomyces coelicolor A3(2): identification of the SigR regulon. Mol Microbiol42:1007–1020
    [Google Scholar]
  46. Pandey D. P., Gerdes K.. 2005; Toxin-antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes. Nucleic Acids Res33:966–976
    [Google Scholar]
  47. Parida S. K., Huygen K., Ryffel B., Chakraborty T.. 2005; Novel bacterial delivery system with attenuated Salmonella typhimurium carrying plasmid encoding Mtb antigen 85A for mucosal immunization: establishment of proof of principle in TB mouse model. Ann N Y Acad Sci1056:366–378
    [Google Scholar]
  48. Parish T., Schaeffer M., Roberts G., Duncan K.. 2005; HemZ is essential for heme biosynthesis in Mycobacterium tuberculosis . Tuberculosis (Edinb85:197–204
    [Google Scholar]
  49. Pinto R., Tang Q. X., Britton W. J., Leyh T. S., Triccas J. A.. 2004; The Mycobacterium tuberculosis cysD and cysNC genes form a stress-induced operon that encodes a tri-functional sulfate-activating complex. Microbiology150:1681–1686
    [Google Scholar]
  50. Provvedi R., Palù G., Manganelli R.. 2008; Use of DNA microarrays to study global patterns of gene expression. In Mycobacteria Protocols , 2nd edn. pp95–110 Edited by Parish T., Brown A. C.. Totowa, NJ: Humana Press;
  51. Raman S., Cascioferro A., Husson R., Manganelli R.. 2008; Mycobacterial sigma factors and surface biology. In The Mycobacterial Cell Envelope pp223–234 Edited by Daffé M., Reyrat J. M. Washington, DC: American Society for Microbiology;
  52. Raviglione M. C.. 2003; The TB epidemic from 1992 to 2002. Tuberculosis (Edinb83:4–14
    [Google Scholar]
  53. Rodrigue S., Provvedi R., Jacques P. E., Gaudreau L., Manganelli R.. 2006; The sigma factors of Mycobacterium tuberculosis . FEMS Microbiol Rev30:926–941
    [Google Scholar]
  54. Schnappinger D., Ehrt S., Voskuil M. I., Liu Y., Mangan J. A., Monahan I. M., Dolganov G., Efron B., Butcher P. D.. other authors 2003; Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment. J Exp Med198:693–704
    [Google Scholar]
  55. Shi L., Jung Y. J., Tyagi S., Gennaro M. L., North R. J.. 2003; Expression of Th1-mediated immunity in mouse lungs induces a Mycobacterium tuberculosis transcription pattern characteristic of nonreplicating persistence. Proc Natl Acad Sci U S A100:241–246
    [Google Scholar]
  56. Soliveri J. A., Gomez J., Bishai W. R., Chater K. F.. 2000; Multiple paralogous genes related to the Streptomyces coelicolor developmental regulatory gene whiB are present in Streptomyces and other actinomycetes. Microbiology146:333–343
    [Google Scholar]
  57. Stewart G. R., Wernisch L., Stabler R., Mangan J. A., Hinds J., Laing K. G., Young D. B., Butcher P. D.. 2002; Dissection of the heat-shock response in Mycobacterium tuberculosis using mutants and microarrays. Microbiology148:3129–3138
    [Google Scholar]
  58. Strong M., Sawaya M. R., Wang S., Phillips M., Cascio D., Eisenberg D.. 2006; Toward the structural genomics of complexes: crystal structure of a PE/PPE protein complex from Mycobacterium tuberculosis . Proc Natl Acad Sci U S A103:8060–8065
    [Google Scholar]
  59. Timm J., Post F. A., Bekker L. G., Walther G. B., Wainwright H. C., Manganelli R., Chan W. T., Tsenova L., Gold B.. other authors 2003; Differential expression of iron-, carbon-, and oxygen-responsive mycobacterial genes in the lungs of chronically infected mice and tuberculosis patients. Proc Natl Acad Sci U S A100:14321–14326
    [Google Scholar]
  60. Tusher V. G., Tibshirani R., Chu G.. 2001; Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A98:5116–5121
    [Google Scholar]
  61. Utaida S., Dunman P. M., Macapagal D., Murphy E., Projan S. J., Singh V. K., Jayaswal R. K., Wilkinson B. J.. 2003; Genome-wide transcriptional profiling of the response of Staphylococcus aureus to cell-wall-active antibiotics reveals a cell-wall-stress stimulon. Microbiology149:2719–2732
    [Google Scholar]
  62. Vaquerizas J. M., Conde L., Yankilevich P., Cabezon A., Minguez P., Diaz-Uriarte R., Al-Shahrour F., Herrero J., Dopazo J.. 2005; GEPAS, an experiment-oriented pipeline for the analysis of microarray gene expression data. Nucleic Acids Res33:W616–W620
    [Google Scholar]
  63. Vipond J., Clark S. O., Hatch G. J., Vipond R., Marie Agger E., Tree J. A., Williams A., Marsh P. D.. 2006; Re-formulation of selected DNA vaccine candidates and their evaluation as protein vaccines using a guinea pig aerosol infection model of tuberculosis. Tuberculosis (Edinb86:218–224
    [Google Scholar]
  64. Voskuil M. I., Visconti K. C., Schoolnik G. K.. 2004; Mycobacterium tuberculosis gene expression during adaptation to stationary phase and low-oxygen dormancy. Tuberculosis (Edinb84:218–227
    [Google Scholar]
  65. Wilson M., DeRisi J., Kristensen H. H., Imboden P., Rane S., Brown P. O., Schoolnik G. K.. 1999; Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization. Proc Natl Acad Sci U S A96:12833–12838
    [Google Scholar]
  66. Zuber B., Chami M., Houssin C., Dubochet J., Griffiths G., Daffé M.. 2008; Direct visualization of the outer membrane of native mycobacteria and corynebacteria. J Bacteriol190:5672–5680
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.024802-0
Loading
/content/journal/micro/10.1099/mic.0.024802-0
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error