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Transcriptomics as a tool to discover new antibacterial targets

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Abstract

The emergence of antibiotic-resistant pathogens, multiple drug-resistance, and extremely drug-resistant strains demonstrates the need for improved strategies to discover new drug-based compounds. The development of transcriptomics, proteomics, and metabolomics has provided new tools for global studies of living organisms. However, the compendium of expression profiles produced by these methods has introduced new scientific challenges into antimicrobial research. In this review, we discuss the practical value of transcriptomic techniques as well as their difficulties and pitfalls. We advocate the construction of new databases of transcriptomic data, using standardized formats in addition to standardized models of bacterial and yeast similar to those used in systems biology. The inclusion of proteomic and metabolomic data is also essential, as the resulting networks can provide a landscape to rationally predict and exploit new drug targets and to understand drug synergies.

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References

  • Allen HK, Donato J, Wang HH, Cloud-Hansen KA, Davies J, Handelsman J (2010) Call of the wild: antibiotic resistance genes in natural environments. Nat Rev Microbiol 4:251–259

    Article  Google Scholar 

  • Austin DJ, Kristinsson KG, Anderson RM (1999) The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proc Nat Acad Sci USA 96:1152–1156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bahn YS (2015) Exploiting fungal virulence-regulating transcription factors as novel antifungal drug targets. PLoS Pathog 11:e1004936

    Article  PubMed  PubMed Central  Google Scholar 

  • Bandow JE, Brötz H, Leichert LI, Labischinski H, Hecker M (2003) Proteomic approach to understanding antibiotic action. Antimicrob Agents Chemother 47:948–955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barbosa TM, Levy SB (2000) The impact of antibiotic use on resistance development and persistence. Drug Resistance Update 5:303–311

    Article  Google Scholar 

  • Bischler T, Tan HS, Nieselt K, Sharma CM (2015) Differential RNA-seq (dRNA-seq) for annotation of transcriptional start sites and small RNAs in Helicobacter pylori. Methods 86:89–101

    Article  CAS  PubMed  Google Scholar 

  • Brazas MD, Hancock RE (2005) Ciprofloxacin induction of a susceptibility determinant in Pseudomonas aeruginosa. Antimicrob Agents Chemother 49:3222–3227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan PF, Macarron R, Payne DJ, Zalacain M, Holmes DJ (2002) Novel antibacterials: a genomics approach to drug discovery. Curr Drug Targ Infect Disord 2:291–308

    Article  CAS  Google Scholar 

  • Chang KC, Kuo HY, Tang CY, Chang CW, Lu CW, Liu CC, Lin HR, Chen KH, Liou ML (2014) Transcriptome profiling in imipenem-selected Acinetobacter baumannii. BMC Genomics 15:815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng G, Li B, Wang C, Zhang H, Liang G, Weng Z, Hao H, Wang X, Liu Z, Dai M, Wang Y, Yuan Z (2015) Systematic and molecular basis of the antibacterial action of quinoxaline 1,4-di-N-oxides against E. coli. PLoS ONE 10:e0136450

    Article  PubMed  PubMed Central  Google Scholar 

  • Christadore M, Pham LL, Kolaczyk ED, Schaus SE (2014) Improvement of experimental testing and network training conditions with genome-wide microarrays for more accurate predictions of drug gene targets. BMC Syst Biol 8:7

    Article  PubMed  PubMed Central  Google Scholar 

  • Coldham NG, Randall LP, Piddock LJ, Woodward MJ (2006) Effect of fluoroquinolone exposure on the proteome of Salmonella enterica serovar Typhimurium. J Antimicrob Chemother 58:1145–1153

    Article  CAS  PubMed  Google Scholar 

  • Conway T, Creecy JP, Maddox SM, Grissom JE, Conkle TL, Shadid TM, Teramoto J, San Miguel P, Shimada T, Ishihama A, Mori H, Wanner BL (2014) Unprecedented high-resolution view of bacterial operon architecture revealed by RNA sequencing. MBio 5:e01442

    Article  PubMed  PubMed Central  Google Scholar 

  • Creecy JP, Conway T (2015) Quantitative bacterial transcriptomics with RNA-seq. Curr Opin Microbiol 23:133–140

    Article  CAS  PubMed  Google Scholar 

  • Debouck C, Goodfellow PN (1999) DNA microarrays in drug discovery and development. Nat Genet 21:48–50

    Article  CAS  PubMed  Google Scholar 

  • Durot M, Bourguignon PY, Schachter V (2009) Genome-scale models of bacterial metabolism: reconstruction and applications. FEMS Microbiol Rev 33:164–190

    Article  CAS  PubMed  Google Scholar 

  • Feng J, Billal DS, Lupien A, Racine G, Winstall E, Légaré D, Leprohon P, Ouellette MJ (2011) Proteomic and transcriptomic analysis of linezolid resistance in S. pneumoniae. J Proteome Res 10:4439–4452

    Article  CAS  PubMed  Google Scholar 

  • 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 14:90–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fournier PE, Vallenet D, Barbe V, Audic S, Ogata H, Poirel L, Richet H, Robert C, Mangenot S, Abergel C, Nordmann P, Weissenbach J, Raoult D, Claverie JM (2006) Comparative genomics of multidrug resistance in A. baumannii. PLoS Genet 2:e7

    Article  PubMed  PubMed Central  Google Scholar 

  • Freiberg C, Brötz-Oesterhelt H, Labischinski H (2004) The impact of transcriptome and proteome analyses on antibiotic drug discovery. Curr Opin Microbiol 5:451–459

    Article  Google Scholar 

  • 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 49:749–759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gautam P, Upadhyay SK, Hassan W, Madan T, Sirdeshmukh R, Sundaram CS, Gade WN, Basir SF, Singh Y, Sarma PU (2011) Transcriptomic and proteomic profile of Aspergillus fumigatus on exposure to artemisinin. Mycopathologia 172:331–346

    Article  CAS  PubMed  Google Scholar 

  • Gibson MK, Crofts TS, Dantas G (2015) Antibiotics and the developing infant gut microbiota and resistome. Curr Opin Microbiol 27:51–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gillings MR (2013) Evolutionary consequences of antibiotic use for the resistome, mobilome and microbial pangenome. Front Microbiol 4:4

    Article  PubMed  PubMed Central  Google Scholar 

  • Goh EB, Yim G, Tsui W, McClureJ Surette MG, Davies J (2002) Transcriptional modulation of bacterial gene expression by subinhibitory concentrations of antibiotics. Proc Nat Acad Sci USA 99:17025–17030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Händel NJ, Schuurmans M, Brul S, ter Kuilea BH (2013) Compensation of the metabolic costs of antibiotic resistance by physiological adaptation in E. coli. Antimicrob Agents Chemother 57:3752–3762

    Article  PubMed  PubMed Central  Google Scholar 

  • Hassan KA, Jackson SM, Penesyan A, Patching SG, Tetu SG, Eijkelkamp BA, Brown MH, Henderson PJF, Paulsena IT (2013) Transcriptomic and biochemical analyses identify a family of chlorhexidine efflux proteins. Proc Natl Acad Sci USA 110:20254–20259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henry R, Crane B, Powell D, Lucas DD, Li Z, Aranda J, Harrison P, Nation RL, Adler B, Harper M, Boyce JD, Li J (2013) The transcriptomic response of Acinetobacter baumannii to colistin and doripenem alone and in combination in an in vitro pharmacokinetics/pharmacodynamics model. J Antimicrob Chemother 70:1303–1313

    Article  Google Scholar 

  • Heo A, Jang H-J, Sung J-S, Park W (2014) Global transcriptome and physiological responses of Acinetobacter oleivorans DR1 exposed to distinct classes of antibiotics. PLoS ONE 9:e110215

    Article  PubMed  PubMed Central  Google Scholar 

  • Hodkinson BP, Grice EA (2015) Next-generation sequencing: a review of technologies and tools for wound microbiome. Res Adv Wound Care 4:50–58

    Article  Google Scholar 

  • Hughes TR, Marton MJ, JonesAR Roberts CJ, Stoughton R, Armour CD, Bennett HA, Coffey E, Dai H, He YD, Kidd MJ, King AM, Meyer MR, Slade D, Lum PY, Stepaniants SB, Shoemaker DD, Gachotte D, Chakraburtty K, Simon J, Bard M, Friend SH (2000) Functional discovery via a compendium of expression profiles. Cell 102:109–126

    Article  CAS  PubMed  Google Scholar 

  • 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 48:2838–2844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ioerger TR, Koo S, No E-G, Chen X, Larsen MH, Jacobs WR Jr, Pillay M, Sturm AW, Sacchettini JC (2009) Genome analysis of multi- and extensively-drug-resistant tuberculosis from KwaZulu-Natal, South Africa. PLoS One 4:e7778

    Article  PubMed  PubMed Central  Google Scholar 

  • Jiang Z, Zhou X, Li R, MichalJJ Zhang S, Dodson MV, Zhang Z, Harland RM (2015) Whole transcriptome analysis with sequencing: methods, challenges and potential solutions. Cell Mol Life Sci 72:3425–3439

    Article  CAS  PubMed  Google Scholar 

  • Johnston M (1998) Gene chips: array of hope for understanding gene regulation. Curr Biol 8:R171–R174

    Article  CAS  PubMed  Google Scholar 

  • Johnston PR, Dobson AJ, Rolff J (2016) Genomic signatures of experimental adaptation to antimicrobial peptides in Staphylococcus aureus. G3: Genes Genomes Genet 6:1535–1539

    Article  Google Scholar 

  • Kozlowska J, Vermeer LS, Rogers GB, Rehnnuma N, Amos SB, Koller G, McArthur M, Bruce KD, Mason AJ (2014) Combined systems approaches reveal highly plastic responses to antimicrobial peptide challenge in E. coli. PLoS Pathog 10:e1004104

    Article  PubMed  PubMed Central  Google Scholar 

  • Kröger C, Colgan A, Srikumar S, Händler K, Sivasankaran SK, Hammarlöf DL, Canals R, Grissom JE, Conway T, Hokamp K, Hinton JC (2013) An infection-relevant transcriptomic compendium for Salmonella enterica serovar Typhimurium. Cell Host Microbe 14:683–695

    Article  PubMed  Google Scholar 

  • Lai LC, Kissinger MT, Burke PV, Kwast KE (2008) Comparison of the transcriptomic “stress response” evoked by antimycin A and oxygen deprivation in Saccharomyces cerevisiae. BMC Genomics 9:627

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee CR, Lee JH, Park KS, Jeong BC, Lee SH (2015) Quantitative proteomic view associated with resistance to clinically important antibiotics in Gram-positive bacteria: a systematic review. Front Microbiol 6:828

    PubMed  PubMed Central  Google Scholar 

  • Lenahan M, Sheridan Á, Morris D, Duffy G, Fanning S, Burgess CM (2014) Transcriptomic analysis of triclosan-susceptible and -tolerant E. coli O157:H19 in response to triclosan exposure. Microb Drug Resistance 20:91–103

    Article  CAS  Google Scholar 

  • Leveringa J, Fiedler T, Sieg A, van Grinsvenc KWA, Hering S, Veitha N, Olivier BG, Klett K, Hugenholtzc J, Teusink B, Kreikemeyer B, Kummer U (2016) Genome-scale reconstruction of the S. pyogenes M49 metabolic network reveals growth requirements and indicates potential drug targets. J Biotechnol 232:25–37

    Article  Google Scholar 

  • Liu Y, Chen P, Wang Y, Li W, Cheng S, Wang C, Zhang A, He Q (2012) Transcriptional profiling of Haemophilus parasuis SH0165 response to tilmicosin. Microb Drug Resistance 18:604–615

    Article  CAS  Google Scholar 

  • Luo Y, Asai K, Sadaie Y, Helmann JD (2010) Transcriptomic and phenotypic characterization of a Bacillus subtilis strain without extracytoplasmic function σ factors. J Bacteriol 192:5736–5745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Melnikow E, Schoenfeld C, Spehr V, Warrass R, Gunkel N, Duszenko M, Selzer PM, Ullrich HJ (2008) A compendium of antibiotic-induced transcription profiles reveals broad regulation of Pasteurella multocida virulence genes. Vet Microbiol 131:277–292

    Article  CAS  PubMed  Google Scholar 

  • Miesel L, Greene J, Blak TA (2003) Genetic strategies for antibacterial drug discovery. Nat Rev Genet 6:442–456

    Article  Google Scholar 

  • Muthaiyan A, Silverman JA, Jayaswal RK, Wilkinson BJ (2008) Transcriptional profiling reveals that daptomycin induces the Staphylococcus aureus cell wall stress stimulon and genes responsive to membrane depolarization. Antimicrob Agents Chemother 52:980–990

    Article  CAS  PubMed  Google Scholar 

  • Navid A (2011) Applications of system-level models of metabolism for analysis of bacterial physiology and identification of new drug targets. Brief Funct Genomics 6:354–364

    Article  Google Scholar 

  • Ng WL, Kazmierczak KM, Robertson GT, Gilmour R, Winkler ME (2003) Transcriptional regulation and signature patterns revealed by microarray analyses of S. pneumoniae R6 challenged with sublethal concentrations of translation inhibitors. J Bacteriol 185:359–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nieto RLM, Mehaffy C, Dobos KM (2016) Comparing isogenic strains of Beijing genotype Mycobacterium tuberculosis after acquisition of Isoniazid resistance: a proteomics approach. Proteomics 9:1376–1380

    Article  Google Scholar 

  • Nomura T, Aiba H, Ishihama A (1985) Transcriptional organization of the convergent overlapping dnaQ-rnh genes of E. coli. J Biol Chem 260:7122–7125

    CAS  PubMed  Google Scholar 

  • O’Keeffe G, Hammel S, Owens RA, Keane TM, Fitzpatrick DA, Jones GW, Doyle S (2014) RNA-seq reveals the pan-transcriptomic impact of attenuating the gliotoxin self-protection mechanism in Aspergillus fumigatus. BMC Genomics 15:894

    Article  PubMed  PubMed Central  Google Scholar 

  • Overton IM, Graham S, Gould KA, Hinds J, Botting CH, Shirran S, Barton GJ, Peter J, Coote PJ (2011) Global network analysis of drug tolerance, mode of action and virulence in methicillin-resistant S. aureus. BMC Syst Biol 5:68

    Article  PubMed  PubMed Central  Google Scholar 

  • Pan Y, Cheng T, Wang Y, Bryant SH (2014) Pathway analysis for drug repositioning based on public database mining. J Chem Inf Model 54:407–418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patkari M, Mehra S (2013) Transcriptomic study of ciprofloxacin resistance in Streptomyces coelicolor A3(2). Mol BioSyst 12:3101–3116

    Article  Google Scholar 

  • Pechous R, Ledala N, Wilkinson BJ, Jayaswal RK (2004) Regulation of the expression of cell wall stress stimulon member gene msrA1 in methicillin-susceptible or -resistant Staphylococcus aureus. Antimicrob Agents Chemother 48:3057–3063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pucci MJ (2006) Use of genomics to select antibacterial targets. Biochem Pharmacol 71:1066–1072

    Article  CAS  PubMed  Google Scholar 

  • Rahmatallah Y, Emmert-Streib F, Glazko G (2016) Gene set analysis approaches for RNA-seq data: performance evaluation and application guideline. Brief Bioinform 3:393–407

    Article  Google Scholar 

  • Sharma CM, Vogel J (2014) Differential RNA-seq: the approach behind and the biological insight gained. Curr Opin Microbiol 19:97–105

    Article  CAS  PubMed  Google Scholar 

  • Sharma CM, Hoffmann S, Darfeuille F, Reignier J, Findeiss S, Sittka A, Chabas S, Reiche K, Hackermüller J, Reinhardt R, Stadler PF, Vogel J (2010) The primary transcriptome of the major human pathogen Helicobacter pylori. Nature 464:250–255

    Article  CAS  PubMed  Google Scholar 

  • Song Y, Rubio A, Jayaswal RK, Silverman JA, Wilkinson BJ (2013) Additional routes to Staphylococcus aureus daptomycin resistance as revealed by comparative genome sequencing, transcriptional profiling, and phenotypic studies. PLoS ONE 8:e58469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Subramanian D, Natarajan J (2015) Network analysis of S. aureus response to ramoplanin reveals modules for virulence factors and resistance mechanisms and characteristic novel genes. Gene 574:149–162

    Article  CAS  PubMed  Google Scholar 

  • Suzuki S, Horinouchi T, Furusawa C (2014) Prediction of antibiotic resistance by gene expression profiles. Nat Commun 5:5792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tally FP, Zeckel M, Wasilewski MM, Carini C, Berman CL, Drusano GL, Oleson FB Jr (1999) Daptomycin: a novel agent for Gram-positive infections. Expert Opin Investig Drugs 8:1223–1238

    Article  CAS  PubMed  Google Scholar 

  • Tavares LS, Silva CS, de Souza VC, da Silva VL, Diniz CG, Santos MO (2013) Strategies and molecular tools to fight antimicrobial resistance: resistome, transcriptome, and antimicrobial peptides. Front Microbiol 4:412

    Article  PubMed  PubMed Central  Google Scholar 

  • Trauner A, Sassetti CM, Rubin EJ (2014). Genetic strategies for identifying new drug targets. Microbiol Spectrum 2: MGM2-0030-2013

  • Utaida S, Dunman PM, Macapagal D, Murphy E, Projan SJ, Singh VK, Jayaswal RK, Wilkinson BJ (2003) Genome-wide transcriptional profiling of the response of Staphylococcus aureus to cell-wall-active antibiotics reveals a cell-wall-stress stimulon. Microbiology 149:2719–2732

    Article  CAS  PubMed  Google Scholar 

  • van Rensburg IC, Loxton AG (2015) Transcriptomics: the key to biomarker discovery during tuberculosis? Future Med 9:483–495

    Google Scholar 

  • Wecke T, Mascher T (2011) Antibiotic research in the age of omics: from expression profiles to interspecies communication. J Antimicrob Chemother 66:2689–2704

    Article  CAS  PubMed  Google Scholar 

  • Wek RC, Hatfield GW (1986) Nucleotide sequence and in vivo expression of the ilvY and ilvC genes in E. coli K12. Transcription from divergent overlapping promoters. J Biol Chem 261:2441–2450

    CAS  PubMed  Google Scholar 

  • Wride DA, Pourmand N, Bray WM, Kosarchuk JJ, Nisam SC, Quan TK, Berkeley RF, Katzman S, Hartzog GA, Dobkin CE, Scott Lokey R (2014) Confirmation of the cellular targets of benomyl and rapamycin using next-generation sequencing of resistant mutants in S. cerevisiae. Mol BioSyst 12:3179–3187

    Article  Google Scholar 

  • Wright MS, Suzuki Y, Jones MB, Marshall SH, Rudin SD, van Duin D, Kaye K, Jacobs MR, Bonomo RA, Adams MD (2015) Genomic and transcriptomic analyses of colistin-resistant clinical isolates of Klebsiella pneumoniae reveal multiple pathways of resistance. Antimicrob Agents Chemother 59:536–543

    Article  PubMed  Google Scholar 

  • Zhou X, Li R, Michal JJ, Wu XL, Liu Z, Zhao H, Xia Y, Du W, Wildung MR, Pouchnik DJ, Harland RM, Jiang Z (2016) Accurate profiling of gene expression and alternative polyadenylation with whole transcriptome termini site sequencing (WTTS-Seq). Genetics 203:683–697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

MV is member of the ENABLE (European Gram Negative Antibacterial Engine) European consortium (IMI-ND4BB, http://www.imi.europa.eu/content/enable). We thank Wendy Ran for copy-editing the manuscript.

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AD conceived of the review and its format. All authors significantly contributed to the content of the article.

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Correspondence to Ángel Domínguez.

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The authors declare that the manuscript was prepared in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Domínguez, Á., Muñoz, E., López, M.C. et al. Transcriptomics as a tool to discover new antibacterial targets. Biotechnol Lett 39, 819–828 (2017). https://doi.org/10.1007/s10529-017-2319-0

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