Advertisement

Applications of transcriptional profiling in antibiotics discovery and development

Chapter
Part of the Progress in Drug Research book series (PDR, volume 64)

Abstract

This chapter will review specific applications of microarray technology and related data analysis strategies in antibacterial research and development. We present examples of microarray applications spanning the entire antibiotics research and development pipeline, from target discovery, assay development, pharmacological evaluation, to compound safety studies. This review emphasizes the utility of microarrays for a systematic evaluation of novel chemistry as antibiotic agents. Transcriptional profiling has revolutionized the process of target elucidation and has the potential to offer substantial guidance in the identification of new targets. Microarrays will continue to be a workhorse of anti-infectives discovery programs ranging from efficacy assessments of antibiotics (‘forward pharmacology’) to drug safety evaluations (‘toxicogenomics’).

Keywords

Lyme Disease Antimicrob Agent Essential Gene Fatty Acid Biosynthesis Reporter Strain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Spellberg B, Powers J, Brass E, Miller L, Edwards J Jr. (2004) Trends in antimicrobial drug development: implications for the future. Clin Infect Dis 38: 1279–1286PubMedCrossRefGoogle Scholar
  2. 2.
    Fleischmann R, Adams M, White O, Clayton R, Kirkness E, Kerlavage A, Bult C, Tomb J, Dougherty B, Merrick J et al (1995) Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 269: 496–512PubMedCrossRefGoogle Scholar
  3. 3.
    Goodman AL, Lory S (2004) Analysis of regulatory networks in Pseudomonas aeruginosa by genomewide transcriptional profiling. Curr Opin Microbiol 7: 39–44PubMedCrossRefGoogle Scholar
  4. 4.
    Conway T, Schoolnik G (2003) Microarray expression profiling: capturing a genome-wide portrait of the transcriptome. Mol Microbiol 47: 879–889PubMedCrossRefGoogle Scholar
  5. 5.
    Grandi G (2003) Rational antibacterial vaccine design through genomic technologies. Int J Parasitol 33: 615–620PubMedCrossRefGoogle Scholar
  6. 6.
    Isolauri E, Salminen S, Ouwehand AC (2004) Probiotics. Best Pract Res Clin Gastroenterol 18: 299–313PubMedCrossRefGoogle Scholar
  7. 7.
    Reid G, Gan BS, She YM, Ens W, Weinberger S, Howard JC (2002) Rapid identification of probiotic lactobacillus biosurfactant proteins by Protein Chip tandem mass spectrometry tryptic peptide sequencing. Appl Environ Microbiol 68: 977–980PubMedCrossRefGoogle Scholar
  8. 8.
    Cui L, Lian JQ, Neoh HM, Reyes E, Hiramatsu K (2005) DNA microarray-based identification of genes associated with glycopeptide resistance in Staphylococcus aureus. Antimicrob Agents Chemother 49: 3404–3413PubMedCrossRefGoogle Scholar
  9. 9.
    Morris RP, Nguyen L, Gatfield J, Visconti K, Nguyen K, Schnappinger D, Ehrt S, Liu Y, Heifets L, Pieters J et al (2005) Ancestral antibiotic resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 102: 12200–12205PubMedCrossRefGoogle Scholar
  10. 10.
    Richmond C, Glasner J, Mau R, Jin H, Blattner F (1999) Genome-wide expression profiling in Escherichia coli K-12. Nucleic Acids Res 27: 3821–3835PubMedCrossRefGoogle Scholar
  11. 11.
    Kane MD, Jatkoe TA, Stumpf CR, Lu J, Thomas JD, Madore SJ (2000) Assessment of the sensitivity and specificity of oligonucleotide (50mer) microarrays. Nucleic Acids Res 28: 4552–4557PubMedCrossRefGoogle Scholar
  12. 12.
    Selinger DW, Saxena RM, Cheung KJ, Church GM, Rosenow C (2003) Global RNA half-life analysis in Escherichia coli reveals positional patterns of transcript degradation. Genome Res 13: 216–223PubMedCrossRefGoogle Scholar
  13. 13.
    Freiberg C, Brunner NA (2002) Genome-wide mRNA profiling: impact on compound evaluation and target identification in anti-bacterial research. Targets 1: 20–29CrossRefGoogle Scholar
  14. 14.
    Gmuender H, Kuratli K, Di Padova K, Gray CP, Keck W, Evers S (2001) Gene expression changes triggered by exposure of Haemophilus influenzae to novobiocin or ciprofloxacin: combined transcription and translation analysis. Genome Res 11: 28–42PubMedCrossRefGoogle Scholar
  15. 15.
    Evers S, Di Padova K, Meyer M, Langen H, Fountoulakis M, Keck W, Gray CP (2001) Mechanism-related changes in the gene transcription and protein synthesis patterns of Haemophilus influenzae after treatment with transcriptional and translational inhibitors. Proteomics 1: 522–544PubMedCrossRefGoogle Scholar
  16. 16.
    Betts J, Lukey P, Robb L, McAdam R, Duncan K (2002) Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol 43: 717–731PubMedCrossRefGoogle Scholar
  17. 17.
    Arfin SM, Long AD, Ito ET, Tolleri L, Riehle MM, Paegle ES, Hatfield GW (2000) Global gene expression profiling in Escherichia coli K12 — The effects of integration host factor. J Biol Chem 275: 29672–29684PubMedCrossRefGoogle Scholar
  18. 18.
    Eymann C, Homuth G, Scharf C, Hecker M (2002) Bacillus subtilis functional genomics: global characterization of the stringent response by proteome and transcriptome analysis. J Bacteriol 184: 2500–2520PubMedCrossRefGoogle Scholar
  19. 19.
    Khodursky AB, Peter BJ, Cozzarelli NR, Botstein D, Brown PO, Yanofsky C (2000) DNA microarray analysis of gene expression in response to physiological and genetic changes that affect tryptophan metabolism in Escherichia coli. Proc Natl Acad Sci USA 97: 12170–12175PubMedCrossRefGoogle Scholar
  20. 20.
    Yoshida K, Kobayashi K, Miwa Y, Kang C, Matsunaga M, Yamaguchi H, Tojo S, Yamamoto M, Nishi R, Ogasawara N et al (2001) Combined transcriptome and proteome analysis as a powerful approach to study genes under glucose repression in Bacillus subtilis. Nucleic Acids Res 29: 683–692PubMedCrossRefGoogle Scholar
  21. 21.
    Bandow JE, Becher D, Buttner K, Hochgrafe F, Freiberg C, Brotz H, Hecker M (2003) The role of peptide deformylase in protein biosynthesis: A proteomic study. Proteomics 3: 299–306PubMedCrossRefGoogle Scholar
  22. 22.
    Bandow JE, Brötz H, Leichert LI, Labischinski H, Hecker M (2003) Proteomic approach to understanding antibiotic action. Antimicrob Agents Chemother 47: 948–955PubMedCrossRefGoogle Scholar
  23. 23.
    Stulke J, Hanschke R, Hecker M (1993) Temporal activation of beta-glucanase synthesis in Bacillus subtilis is mediated by the GTP pool. J GenMicrobiol 139 (Pt 9): 2041–2045Google Scholar
  24. 24.
    Freiberg C, Fischer HP, Brunner NA (2005) Discovering the mechanism of action of novel antibacterial agents through transcriptional profiling of conditional mutants. Antimicrob Agents Chemother 49: 749–759PubMedCrossRefGoogle Scholar
  25. 25.
    Hutter B, Schaab C, Albrecht S, Borgmann M, Brunner NA, Freiberg C, Ziegelbauer K, Rock CO, Ivanov I, Loferer H (2004) Prediction of mechanisms of action of antibacterial compounds by gene expression profiling. Antimicrob Agents Chemother 48: 2838–2844PubMedCrossRefGoogle Scholar
  26. 26.
    Betts JC, McLaren A, Lennon MG, Kelly FM, Lukey PT, Blakemore SJ, Duncan K (2003) Signature gene expression profiles discriminate between isoniazid-, thiolactomycin-, and triclosan-treated Mycobacterium tuberculosis. Antimicrob Agents Chemother 47: 2903–2913PubMedCrossRefGoogle Scholar
  27. 27.
    Gunther EC, Stone DJ, Gerwien RW, Bento P, Heyes MP, Staunton JE, Slonim DK, Coller HA, Tamayo P, Angelo MJ et al (2003) Prediction of clinical drug efficacy by classification of drug-induced genomic expression profiles in vitro. Proc Natl Acad Sci USA 100: 9608–9613PubMedCrossRefGoogle Scholar
  28. 28.
    Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M et al (2001) Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA 98: 13790–13795PubMedCrossRefGoogle Scholar
  29. 29.
    Staunton JE, Slonim DK, Coller HA, Tamayo P, Angelo MJ, Park J, Scherf U, Lee JK, Reinhold WO, Weinstein JN et al (2001) Chemosensitivity prediction by transcriptional profiling. Proc Natl Acad Sci USA 98: 10787–10792PubMedCrossRefGoogle Scholar
  30. 30.
    Ramaswamy S, Tamayo P, Rifkin R, Mukherjee S, Yeang CH, Angelo M, Ladd C, Reich M, Latulippe E, Mesirov JP et al (2001) Multiclass cancer diagnosis using tumor gene expression signatures. Proc Natl Acad Sci USA 98: 15149–15154PubMedCrossRefGoogle Scholar
  31. 31.
    Boshoff HI, Myers TG, Copp BR, McNeil MR, Wilson MA, Barry CE 3rd (2004) The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. J Biol Chem 279: 40174–40184PubMedCrossRefGoogle Scholar
  32. 32.
    Revel A, Talaat A, Norgard M (2002) DNA microarray analysis of differential gene expression in Borrelia burgdorferi, the Lyme disease spirochete. Proc Natl Acad Sci USA 99: 1562–1567PubMedCrossRefGoogle Scholar
  33. 33.
    Hentzer M, Wu H, Andersen JB, Riedel K, Rasmussen TB, Bagge N, Kumar N, Schembri MA, Song Z, Kristoffersen P et al (2003) Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. Embo J 22: 3803–3815PubMedCrossRefGoogle Scholar
  34. 34.
    Rasmussen TB, Skindersoe ME, Bjarnsholt T, Phipps RK, Christensen KB, Jensen PO, Andersen JB, Koch B, Larsen TO, Hentzer et al (2005) Identity and effects of quorum-sensing inhibitors produced by Penicillium species. Microbiology 151: 1325–1340PubMedCrossRefGoogle Scholar
  35. 35.
    Freiberg C, Brotz-Oesterhelt H (2005) Functional genomics in antibacterial drug discovery. Drug Discov Today 10: 927–935PubMedCrossRefGoogle Scholar
  36. 36.
    Miesel L, Greene J, Black TA (2003) Genetic strategies for antibacterial drug discovery. Nat Rev Genet 4: 442–456PubMedCrossRefGoogle Scholar
  37. 37.
    Moir DT, Shaw KJ, Hare RS, Vovis GF (1999) Genomics and antimicrobial drug discovery. Antimicrob Agents Chemother 43: 439–446PubMedGoogle Scholar
  38. 38.
    di Bernardo D, Thompson MJ, Gardner TS, Chobot SE, Eastwood EL, Wojtovich AP, Elliott SJ, Schaus SE, Collins JJ (2005) Chemogenomic profiling on a genome-wide scale using reverse-engineered gene networks. Nat Biotechnol 23: 377–383PubMedCrossRefGoogle Scholar
  39. 39.
    Gerhold DL, Jensen RV, Gullans SR (2002) Better therapeutics through microarrays. Nat Genet 32Suppl: 547–551PubMedCrossRefGoogle Scholar
  40. 40.
    Shaw KJ, Miller N, Liu X, Lerner D, Wan J, Bittner A, Morrow BJ (2003) Comparison of the changes in global gene expression of Escherichia coli induced by four bactericidal agents. J Mol Microbiol Biotechnol 5: 105–122PubMedCrossRefGoogle Scholar
  41. 41.
    Wilson M, DeRisi J, Kristensen HH, Imboden P, Rane S, Brown PO, Schoolnik GK (1999) Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization. ProcNatl Acad Sci USA 96: 12833–12838CrossRefGoogle Scholar
  42. 42.
    Sabina J, Dover N, Templeton LJ, Smulski DR, Soll D, LaRossa RA (2003) Interfering with different steps of protein synthesis explored by transcriptional profiling of Escherichia coli K-12. J Bacteriol 185: 6158–6170PubMedCrossRefGoogle Scholar
  43. 43.
    Ng WL, Kazmierczak KM, Robertson GT, Gilmour R, Winkler ME (2003) Transcriptional regulation and signature patterns revealed by microarray analyses of Streptococcus pneumoniae R6 challenged with sublethal concentrations of translation inhibitors. J Bacteriol 185: 359–370PubMedCrossRefGoogle Scholar
  44. 44.
    Brazas MD, Hancock RE (2005) Using microarray gene signatures to elucidate mechanisms of antibiotic action and resistance. Drug Discov Today 10: 1245–1252PubMedCrossRefGoogle Scholar
  45. 45.
    Brazas MD, Hancock RE (2005) Ciprofloxacin induction of a susceptibility determinant in Pseudomonas aeruginosa. Antimicrob Agents Chemother 49: 3222–3227PubMedCrossRefGoogle Scholar
  46. 46.
    Hughes TR, Marton MJ, Jones AR, Roberts CJ, Stoughton R, Armour CD, Bennett HA, Coffey E, Dai H, He YD et al (2000) Functional discovery via a compendium of expression profiles. Cell 102: 109–126PubMedCrossRefGoogle Scholar
  47. 47.
    Mnaimneh S, Davierwala AP, Haynes J, Moffat J, Peng WT, Zhang W, Yang X, Pootoolal J, Chua G, Lopez A et al (2004) Exploration of essential gene functions via titratable promoter alleles. Cell 118: 31–44PubMedCrossRefGoogle Scholar
  48. 48.
    Freiberg C, Schiffer G, Brunner N, Lampe T, Pohlmann J, Brands M, Haebich D, Ziegelbauer K (2004) Identification and characterization of the first class of potent bacterial acetyl-CoA carboxylase inhibitors with antibacterial activity. J Biol Chem 279: 26066–26073PubMedCrossRefGoogle Scholar
  49. 49.
    Fischer HP, Brunner NA, Wieland B, Paquette J, Macko L, Ziegelbauer K, Freiberg C (2004) Identification of antibiotic stress-inducible promoters: a systematic approach to novel pathway-specific reporter assays for antibacterial drug discovery. Genome Res 14: 90–98PubMedCrossRefGoogle Scholar
  50. 50.
    Hutter B, Fischer C, Jacobi A, Schaab C, Loferer H (2004) Panel of Bacillus subtilis reporter strains indicative of various modes of action. Antimicrob Agents Chemother 48: 2588–2594PubMedCrossRefGoogle Scholar
  51. 51.
    Mascher T, Zimmer SL, Smith TA, Helmann JD (2004) Antibiotic-inducible promoter regulated by the cell envelope stress-sensing two-component system LiaRS of Bacillus subtilis. Antimicrob Agents Chemother 48: 2888–2896PubMedCrossRefGoogle Scholar
  52. 52.
    Alksne LE, Burgio P, Hu W, Feld B, Singh MP, Tuckman M, Petersen PJ, Labthavikul P, McGlynn M, Barbieri L et al (2000) Identification and analysis of bacterial protein secretion inhibitors utilizing a SecA-LacZ reporter fusion system. Antimicrob Agents Chemother 44: 1418–1427PubMedCrossRefGoogle Scholar
  53. 53.
    Bianchi AA, Baneyx F (1999) Stress responses as a tool to detect and characterize the mode of action of antibacterial agents. Appl Environ Microbiol 65: 5023–5027PubMedGoogle Scholar
  54. 54.
    Cao M, Salzberg L, Tsai CS, Mascher T, Bonilla C, Wang T, Ye RW, Marquez-Magana L, Helmann JD (2003) Regulation of the Bacillus subtilis extracytoplasmic function protein sigma(Y) and its target promoters. J Bacteriol 185: 4883–4890PubMedCrossRefGoogle Scholar
  55. 55.
    Shapiro E, Baneyx F (2002) Stress-based identification and classification of antibacterial agents: Second-generation Escherichia coli reporter strains and optimization of detection. Antimicrob Agents Chemother 46: 2490–2497PubMedCrossRefGoogle Scholar
  56. 56.
    Sun D, Cohen S, Mani N, Murphy C, Rothstein DM (2002) A pathway-specific cell based screening system to detect bacterial cell wall inhibitors. J Antibiot (Tokyo) 55: 279–287Google Scholar
  57. 57.
    Smulski DR, Huang LL, McCluskey MP, Reeve MJG, Vollmer AC, Van Dyk TK, LaRossa RA (2001) Combined, functional genomic-biochemical approach to intermediary metabolism: Interaction of acivicin, a glutamine amidotransferase inhibitor, with Escherichia coli K-12. J Bacteriology 183: 3353–3364CrossRefGoogle Scholar
  58. 58.
    Ulrich RG, Rockett JC, Gibson GG, Pettit SD (2004) Overview of an interlaboratory collaboration on evaluating the effects of model hepatotoxicants on hepatic gene expression. Environ Health Perspect 112: 423–427PubMedGoogle Scholar
  59. 59.
    Waring JF, Halbert DN (2002) The promise of toxicogenomics. Curr Opin Mol Ther 4: 229–235PubMedGoogle Scholar
  60. 60.
    Kramer JA, Pettit SD, Amin RP, Bertram TA, Car B, Cunningham M, Curtiss SW, Davis JW, Kind C, Lawton M et al (2004) Overview on the application of transcription profiling using selected nephrotoxicants for toxicology assessment. Environ Health Perspect 112: 460–464PubMedGoogle Scholar
  61. 61.
    Hamadeh HK, Bushel PR, Jayadev S, Martin K, DiSorbo O, Sieber S, Bennett L, Tennant R, Stoll R, Barrett JC et al (2002) Gene expression analysis reveals chemical-specific profiles. Toxicol Sci 67: 219–231PubMedCrossRefGoogle Scholar
  62. 62.
    Amin RP, Vickers AE, Sistare F, Thompson KL, Roman RJ, Lawton M, Kramer J, Hamadeh HK, Collins J, Grissom S et al (2004) Identification of putative gene based markers of renal toxicity. Environ Health Perspect 112: 465–479PubMedCrossRefGoogle Scholar
  63. 63.
    Waring JF, Jolly RA, Ciurlionis R, Lum PY, Praestgaard JT, Morfitt DC, Buratto B, Roberts C, Schadt E, Ulrich RG (2001) Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles. Toxicol Appl Pharmacol 175: 28–42PubMedCrossRefGoogle Scholar
  64. 64.
    Ellinger-Ziegelbauer H, Stuart B, Wahle B, Bomann W, Ahr HJ (2004) Characteristic expression profiles induced by genotoxic carcinogens in rat liver. Toxicol Sci 77: 19–34PubMedCrossRefGoogle Scholar
  65. 65.
    Ellinger-Ziegelbauer H, Stuart B, Wahle B, Bomann W, Ahr HJ (2005) Comparison of the expression profiles induced by genotoxic and nongenotoxic carcinogens in rat liver. Mutat Res 575: 61–84PubMedGoogle Scholar
  66. 66.
    Liguori MJ, Anderson LM, Bukofzer S, McKim J, Pregenzer JF, Retief J, Spear BB, Waring JF (2005) Microarray analysis in human hepatocytes suggests a mechanism for hepatotoxicity induced by trovafloxacin. Hepatology 41: 177–186PubMedCrossRefGoogle Scholar
  67. 67.
    Salama N, Guillemin K, McDaniel TK, Sherlock G, Tompkins L, Falkow S (2000) A whole-genome microarray reveals genetic diversity among Helicobacter pylori strains. Proc Natl Acad Sci USA 97: 14668–14673PubMedCrossRefGoogle Scholar
  68. 68.
    Marshall BJ, Warren JR (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1: 1311–1315PubMedCrossRefGoogle Scholar
  69. 69.
    Go MF (2002) Review article: natural history and epidemiology of Helicobacter pylori infection. Aliment Pharmacol Ther 16Suppl 1: 3–15PubMedCrossRefGoogle Scholar
  70. 70.
    Cordwell S, Nouwens A, Walsh B (2001) Comparative proteomics of bacterial pathogens. Proteomics 1: 461–472PubMedCrossRefGoogle Scholar
  71. 71.
    Klade CS (2002) Proteomics approaches towards antigen discovery and vaccine development. Curr Opin Mol Ther 4: 216–223PubMedGoogle Scholar
  72. 72.
    Serruto D, Adu-Bobie J, Capecchi B, Rappuoli R, Pizza M, Masignani V (2004) Biotechnology and vaccines: application of functional genomics to Neisseria meningitidis and other bacterial pathogens. J Biotechnol 113: 15–32PubMedCrossRefGoogle Scholar
  73. 73.
    Schmid JW, Mauch K, Reuss M, Gilles ED, Kremling A (2004) Metabolic design based on a coupled gene expression-metabolic network model of tryptophan production in Escherichia coli. Metab Eng 6: 364–377PubMedCrossRefGoogle Scholar
  74. 74.
    Swameye I, Muller TG, Timmer J, Sandra O, Klingmuller U (2003) Identification of nucleocytoplasmic cycling as a remote sensor in cellular signaling by databased modeling. Proc Natl Acad Sci USA 100: 1028–1033PubMedCrossRefGoogle Scholar
  75. 75.
    Reed JL, Vo TD, Schilling CH, Palsson BO (2003) An expanded genome-scale model of Escherichia coli K-12 (iJR904 GSM/GPR). Genome Biol 4: R54PubMedCrossRefGoogle Scholar
  76. 76.
    Koffas M, Stephanopoulos G (2005) Strain improvement by metabolic engineering: lysine production as a case study for systems biology. Curr Opin Biotechnol 16: 361–366PubMedCrossRefGoogle Scholar
  77. 77.
    Lee WC, Lee KH (2004) Applications of affinity chromatography in proteomics. Anal Biochem 324: 1–10PubMedCrossRefGoogle Scholar
  78. 78.
    Jonsson P, Johansson AI, Gullberg J, Trygg J, A J, Grung B, Marklund S, Sjostrom M, Antti H, Moritz T (2005) High-throughput data analysis for detecting and identifying differences between samples in GC/MS-based metabolomic analyses. Anal Chem 77: 5635–5642PubMedCrossRefGoogle Scholar
  79. 79.
    Shimizu K (2004) Metabolic flux analysis based on 13C-labeling experiments and integration of the information with gene and protein expression patterns. Adv Biochem Eng Biotechnol 91: 1–49PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag 2007

Authors and Affiliations

  1. 1.Genedata AGBaselSwitzerland
  2. 2.Pharma Research & DevelopmentBayer HealthCare AGGermany

Personalised recommendations

Cite chapter

Buy options