Advertisement
Research Article| Volume 54, ISSUE 3, P277-284, March 2007

Genome-wide exploration of the drug action of capreomycin on Mycobacterium tuberculosis using Affymetrix oligonucleotide GeneChips

      Summary

      Objective

      Multi-drug resistance and latent infection are two major issues in current tuberculosis (TB) control and management. Capreomycin is an important drug used for TB with multi-drug resistance. A recent study also indicates that this drug possesses unique bactericidal activity against non-replicating TB bacilli among known anti-TB drugs. Thus, there is an urgent need for investigating the full-spectrum action of capreomycin.

      Methods

      Here we conduct the first microarray-based study on capreomycin using the high-resolution Affymetrix oligonucleotide GeneChip system.

      Results

      The results indicate that capreomycin primarily acts on the information pathways but it also significantly affects cell wall, cell processes, intermediate metabolism and respiration in Mycobacterium tuberculosis.

      Conclusions

      This study not only transcriptionally validates the specific molecular target, 16S rRNA, but also discovers potential new targets of capreomycin, including genes operating at the DNA level, such as Rv0054 (ssb) and Rv3715c (recR), as well as genes involved in cell division like Rv3260c (whiB2). In addition, the nuo gene cluster and the ATP synthase gene cluster are repressed.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Infection
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Johnson J.L.
        • Ellner J.J.
        Adult tuberculosis overview: African versus Western perspectives.
        Curr Opin Pulm Med. 2000; 6: 180-186
        • Seaworth B.J.
        Multidrug-resistant tuberculosis.
        Infect Dis Clin North Am. 2002; 16: 73-105
        • Blumberg H.M.
        • Leonard Jr., M.K.
        • Jasmer R.M.
        Update on the treatment of tuberculosis and latent tuberculosis infection.
        JAMA. 2005; 293: 2776-2784
        • Khan K.
        • Muennig P.
        • Behta M.
        • Zivin J.G.
        Global drug-resistance patterns and the management of latent tuberculosis infection in immigrants to the United States.
        N Engl J Med. 2002; 347: 1850-1859
        • Zierski M.
        Capreomycin and other drugs in the treatment of pulmonary tuberculosis.
        Tubercle. 1969; 50: 37-39
        • Rastogi N.
        • Labrousse V.
        • Goh K.S.
        In vitro activities of fourteen antimicrobial agents against drug susceptible and resistant clinical isolates of Mycobacterium tuberculosis and comparative intracellular activities against the virulent H37Rv strain in human macrophages.
        Curr Microbiol. 1996; 33: 167-175
        • Heifets L.
        • Simon J.
        • Pham V.
        Capreomycin is active against non-replicating M. tuberculosis.
        Ann Clin Microbiol Antimicrob. 2005; 4: 6
        • Maus C.E.
        • Plikaytis B.B.
        • Shinnick T.M.
        Mutation of tlyA confers capreomycin resistance in Mycobacterium tuberculosis.
        Antimicrob Agents Chemother. 2005; 49: 571-577
        • Wilson M.
        • DeRisi J.
        • Kristensen H.H.
        • Imboden P.
        • Rane S.
        • Brown P.O.
        • et al.
        Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization.
        Proc Natl Acad Sci USA. 1999; 96: 12833-12838
        • Li J.
        • Pankratz M.
        • Johnson J.A.
        Differential gene expression patterns revealed by oligonucleotide versus long cDNA arrays.
        Toxicol Sci. 2002; 69: 383-390
        • Waddell S.J.
        • Stabler R.A.
        • Laing K.
        • Kremer L.
        • Reynolds R.C.
        • Besra G.S.
        The use of microarray analysis to determine the gene expression profiles of Mycobacterium tuberculosis in response to anti-bacterial compounds.
        Tuberculosis (Edinb). 2004; 84: 263-274
        • Fisher M.A.
        • Plikaytis B.B.
        • Shinnick T.M.
        Microarray analysis of the Mycobacterium tuberculosis transcriptional response to the acidic conditions found in phagosomes.
        J Bacteriol. 2002; 184: 4025-4032
        • Cole S.T.
        • Brosch R.
        • Parkhill J.
        • Garnier T.
        • Churcher C.
        • Harris D.
        • et al.
        Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence.
        Nature. 1998; 393: 537-544
        • Tavazoie S.
        • Hughes J.D.
        • Campbell M.J.
        • Cho R.J.
        • Church G.M.
        Systematic determination of genetic network architecture.
        Nat Genet. 1999; 22: 281-285
        • Boshoff H.I.
        • Myers T.G.
        • Copp B.R.
        • McNeil M.R.
        • Wilson M.A.
        • Barry 3rd., C.E.
        The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action.
        J Biol Chem. 2004; 279: 40174-40184
        • Gomez J.E.
        • Bishai W.R.
        whmD is an essential mycobacterial gene required for proper septation and cell division.
        Proc Natl Acad Sci USA. 2000; 97: 8554-8559
        • McKinney J.D.
        • Honer zu Bentrup K.
        • Munoz-Elias E.J.
        • Miczak A.
        • Chen B.
        • Chan W.T.
        • et al.
        Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase.
        Nature. 2000; 406: 735-738
        • Betts J.C.
        • Lukey P.T.
        • Robb L.C.
        • McAdam R.A.
        • Duncan K.
        Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling.
        Mol Microbiol. 2002; 43: 717-731
        • Sherman D.R.
        • Voskuil M.
        • Schnappinger D.
        • Liao R.
        • Harrell M.I.
        • Schoolnik G.K.
        Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha -crystallin.
        Proc Natl Acad Sci USA. 2001; 98: 7534-7539
        • Rodriguez G.M.
        • Voskuil M.I.
        • Gold B.
        • Schoolnik G.K.
        • Smith I.
        ideR, An essential gene in Mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response.
        Infect Immun. 2002; 70: 3371-3381
        • Sassetti C.M.
        • Boyd D.H.
        • Rubin E.J.
        Genes required for mycobacterial growth defined by high density mutagenesis.
        Mol Microbiol. 2003; 48: 77-84
        • DeRisi J.L.
        • Iyer V.R.
        • Brown P.O.
        Exploring the metabolic and genetic control of gene expression on a genomic scale.
        Science. 1997; 278: 680-686
        • Paunescu E.
        • Stoinescu M.
        • Zaharescu C.
        • Dragusanu E.
        Some correlations between chemical structure and mode of action of tuberculostatica. Researches on capreomycin and isoxyl.
        Antibiot Chemother. 1970; 16: 10-16
        • Yamada T.
        • Mizuguchi Y.
        • Suga K.
        Localization of co-resistance to streptomycin, kanamycin, capreomycin, and tuberactinomycin in core particles derived from ribosomes of viomycin-resistant Mycobacterium smegmatis.
        J Antibiot (Tokyo). 1976; 29: 1124-1126
        • Yamada T.
        • Bierhaus K.H.
        Viomycin favours the formation of 70S ribosome couples.
        Mol Gen Genet. 1978; 161: 261-265
        • Modolell J.
        • Vazquez
        The inhibition of ribosomal translocation by viomycin.
        Eur J Biochem. 1977; 81: 491-497
        • Suzuki Y.
        • Katsukawa C.
        • Tamaru A.
        • Abe C.
        • Makino M.
        • Mizuguchi Y.
        • et al.
        Detection of kanamycin-resistant Mycobacterium tuberculosis by identifying mutations in the 16S rRNA gene.
        J Clin Microbiol. 1998; 36: 1220-1225
        • Maus C.E.
        • Plikaytis B.B.
        • Shinnick T.M.
        Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin, and viomycin in Mycobacterium tuberculosis.
        Antimicrob Agents Chemother. 2005; 49: 3192-3197
        • Buriankova K.
        • Doucet-Populaire F.
        • Dorson O.
        • Gondran A.
        • Ghnassia J.C.
        • Weiser J.
        • et al.
        Molecular basis of intrinsic macrolide resistance in the Mycobacterium tuberculosis complex.
        Antimicrob Agents Chemother. 2004; 48: 143-150
        • Onodera Y.
        • Tanaka M.
        • Sato K.
        Inhibitory activity of quinolones against DNA gyrase of Mycobacterium tuberculosis.
        J Antimicrob Chemother. 2001; 47: 447-450
        • Ng W.L.
        • Kazmierczak K.M.
        • Robertson G.T.
        • Gilmour R.
        • Winkler M.E.
        Transcriptional regulation and signature patterns revealed by microarray analyses of Streptococcus pneumoniae R6 challenged with sublethal concentrations of translation inhibitors.
        J Bacteriol. 2003; 185: 359-370
        • Denkin S.
        • Byrne S.
        • Jie C.
        • Zhang Y.
        Gene expression profiling analysis of Mycobacterium tuberculosis genes in response to salicylate.
        Arch Microbiol. 2005; 184: 152-157
        • Fu L.M.
        Exploring drug action on Mycobacterium tuberculosis using affymetrix oligonucleotide genechips.
        Tuberculosis (Edinb). 2006; 86: 134-143
        • Behr M.A.
        • Wilson M.A.
        • Gill W.P.
        • Salamon H.
        • Schoolnik G.K.
        • Rane S.
        • et al.
        Comparative genomics of BCG vaccines by whole-genome DNA microarray.
        Science. 1999; 284: 1520-1523
        • Kato-Maeda M.
        • Rhee J.T.
        • Gingeras T.R.
        • Salamon H.
        • Drenkow J.
        • Smittipat N.
        • et al.
        Comparing genomes within the species Mycobacterium tuberculosis.
        Genome Res. 2001; 11: 547-554
        • Tsolaki A.G.
        • Hirsh A.E.
        • DeRiemer K.
        • Enciso J.A.
        • Wong M.Z.
        • Hannan M.
        • et al.
        Functional and evolutionary genomics of Mycobacterium tuberculosis: insights from genomic deletions in 100 strains.
        Proc Natl Acad Sci USA. 2004; 101: 4865-4870
        • Schnappinger D.
        • Ehrt S.
        • Voskuil M.I.
        • Liu Y.
        • Mangan J.A.
        • Monahan I.M.
        • et al.
        Transcriptional Adaptation of Mycobacterium tuberculosis within Macrophages: Insights into the Phagosomal Environment.
        J Exp Med. 2003; 198: 693-704