Abstract
Understanding how complex phenotypes arise from individual molecules and their interactions is a primary challenge in biology, and computational approaches have been increasingly employed to tackle this task. In this chapter, we describe current efforts by FIOCRUZ and partners to develop integrated computational models of multidrug-resistant bacteria. The bacterium chosen as the main focus of this effort is Pseudomonas aeruginosa, an opportunistic pathogen associated with a broad spectrum of infections in humans. Nowadays, P. aeruginosa is one of the main problems of healthcare-associated infections (HAI) in the world, because of its great capacity of survival in hospital environments and its intrinsic resistance to many antibiotics. Our overall research objective is to use integrated computational models to accurately predict a wide range of observable cellular behaviors of multidrug-resistant P. aeruginosa CCBH4851, which is a strain belonging to the clone ST277, endemic in Brazil. In this chapter, after a brief introduction to P. aeruginosa biology, we discuss the construction of metabolic and gene regulatory networks of P. aeruginosa CCBH 4851 from its genome. We also illustrate how these networks can be integrated into a single model, and we discuss methods for identifying potential therapeutic targets through integrated models.
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References
Brasil. Ministério da Saúde. Agência Nacional de Vigilância Sanitária. Boletim de segurança do paciente e qualidade em serviços de saúde n° 14: Avaliação dos indicadores nacionais das Infecções Relacionadas à Assistência à Saúde (IRAS) e resistência microbiana do ano de 2015. Brasília (DF): Ministério da Saúde. (In portuguese) Available at: (https://www20.anvisa.gov.br/segurancadopaciente/index.php/publicacoes/item/boletim-de-seguranca-do-paciente-e-qualidade-em-servicos-de-saude-n-13-avaliacao-dos-indicadores-nacionais-das-infeccoes-relacionadas-a-assistencia-a-saude-iras-e-resistencia-microbiana-do-ano-de-2015) 2016.
World Health Organization. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. (http://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf?ua=1) 2017.
Covert M, Xiao N, Chen T, Karr J. Integrating metabolic, transcriptional regulatory and signal transduction models in Escherichia coli. Bioinformatics. 2008;24(18):2044–50.
Silveira M, Albano R, Asensi M, Assef A. The draft genome sequence of multidrug-resistant Pseudomonas aeruginosa strain CCBH4851, a nosocomial isolate belonging to clone SP (ST277) that is prevalent in Brazil. Mem Inst Oswaldo Cruz. 2014;109(8):1086–7.
Carrera J, Covert M. Why build whole-cell models? Trends Cell Biol. 2015;25(12):719–22.
Karr J, Sanghvi J, Macklin D, Gutschow M, Jacobs J, Bolival B, et al. A whole-cell computational model predicts phenotype from genotype. Cell. 2012;150(2):389–401.
Pier GB, Ramphal R. Pseudomonas aeruginosa. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. Philadelphia: Churchill Livingstone Elsevier; 2010. p. 2835–60.
Driscoll J, Brody S, Kollef M. The epidemiology, pathogenesis and treatment of Pseudomonas aeruginosa infections. Drugs. 2007;67(3):351–68.
Lee K, Yoon SS. Pseudomonas aeruginosa biofilm, a programmed bacterial life for fitness. J Microbiol Biotechnol. 2017;27(6):1053–64.
Balasubramanian D, Schneper L, Kumari H, Mathee K. A dynamic and intricate regulatory network determines Pseudomonas aeruginosa virulence. Nucleic Acids Res. 2012;41(1):1–20.
Engel J, Balachandran P. Role of Pseudomonas aeruginosa type III effectors in disease. Curr Opin Microbiol. 2009;12(1):61–6.
Tomita M, Hashimoto K, Takahashi K, Shimizu TS, Matsuzaki Y, Miyoshi F, Saio K, Tanida S, Yugi K, Venter J, Hutchison CA. E-CELL: software environment for whole-cell simulation. Bioinformatics. 1999;15(1):72–84.
Kerr K, Snelling A. Pseudomonas aeruginosa: a formidable and ever-present adversary. J Hosp Infect. 2009;73(4):338–44.
Kung V, Ozer E, Hauser A. The accessory genome of Pseudomonas aeruginosa. Microbiol Mol Biol Rev. 2010;74(4):621–41.
Vallet-Gely I, Boccard F. Chromosomal organization and segregation in Pseudomonas aeruginosa. PLoS Genet. 2013;9(5):e1003492.
Silveira M, Albano R, Asensi M, Carvalho-Assef A. Description of genomic islands associated to the multidrug-resistant Pseudomonas aeruginosa clone ST277. Infect Genet Evol. 2016;42:60–5.
Oliver A, Mulet X, López-Causapé C, Juan C. The increasing threat of Pseudomonas aeruginosa high-risk clones. Drug Resist Updat. 2015;21–22:41–59.
Cornaglia G, Giamarellou H, Rossolini G. Metallo-β-lactamases: a last frontier for β-lactams? Lancet Infect Dis. 2011;11(5):381–93.
Nascimento A, Ortiz M, Martins W, Morais G, Fehlberg L, Almeida L, et al. Intraclonal genome stability of the metallo-β-lactamase SPM-1-producing Pseudomonas aeruginosa ST277, an endemic clone disseminated in brazilian hospitals. Front Microbiol. 2016;7:1946.
Cavalcanti F, Almeida A, Vilela M, Morais M, Morais JM. Changing the epidemiology of carbapenem-resistant Pseudomonas aeruginosa in a Brazilian teaching hospital: the replacement of São Paulo metallo-β-lactamase-producing isolates. Mem Inst Oswaldo Cruz. 2012;107(3):420–3.
Gales A, Menezes L, Silbert S, Sader H. Dissemination in distinct Brazilian regions of an epidemic carbapenem-resistant Pseudomonas aeruginosa producing SPM metallo- β-lactamase. J Antimicrob Chemother. 2003;52(4):699–702.
Fonseca E, Freitas F, Vicente A. The Colistin-only sensitive Brazilian Pseudomonas aeruginosa clone SP (sequence type 277) is spread worldwide. Antimicrob Agents Chemother. 2010;54(6):2743.
Salabi A, Toleman M, Weeks J, Bruderer T, Frei R, Walsh T. First report of the metallo- β-lactamase SPM-1 in Europe. Antimicrob Agents Chemother. 2009;54(1):582.
Hopkins K, Findlay J, Mustafa N, Pike R, Parsons H, Wright L, et al. SPM-1 metallo-β-lactamase-producing Pseudomonas aeruginosa ST277 in the UK. J Med Microbiol. 2016;65(7):696–7.
Galán-Vásquez E, Luna B, Martínez-Antonio A. The regulatory network of Pseudomonas aeruginosa. Microb Inf Exp. 2011;1(1):3.
Babaei P, Ghasemi-Kahrizsangi T, Marashi S. Modeling the differences in biochemical capabilities of pseudomonas species by flux balance analysis: how good are genome-scale metabolic networks at predicting the differences? Sci World J. 2014;2014:1–11.
Brent M. Genome annotation past, present, and future: how to define an ORF at each locus. Genome Res. 2005;15(12):1777–86.
Richardson E, Watson M. The automatic annotation of bacterial genomes. Brief Bioinform. 2012;14(1):1–12.
Verli H. Bioinformática: da biologia à flexibilidade molecular. 1st ed. São Paulo: SBBq; 2014.
Campbell M, Yandell M. An introduction to genome annotation. Curr Protocol Bioinforma. 2015;52:4.1.1–4.1.17.
Delcher A. Improved microbial gene identification with GLIMMER. Nucleic Acids Res. 1999;27(23):4636–41.
Besemer J, Lomsadze A, Borodovsky M. GeneMarkS: a self-training method for prediction of gene starts in microbial genomes. Implications for finding sequence motifs in regulatory regions. Nucleic Acids Res. 2001;29(12):2607–18.
Tatusova T, DiCuccio M, Badretdin A, Chetvernin V, Nawrocki E, Zaslavsky L, et al. NCBI prokaryotic genome annotation pipeline. Nucleic Acids Res. 2016;44(14):6614–24.
Lagesen K, Hallin P, Rødland E, Stærfeldt H, Rognes T, Ussery D. RNAmmer: consistent and rapid annotation of ribosomal RNA genes. Nucleic Acids Res. 2007;35(9):3100–8.
Lowe T, Eddy S. tRNAscan-SE: a program for improved detection of transfer RNA genes in genomic sequence. Nucleic Acids Res. 1997;25(5):955–64.
Laslett D, Canback B. ARAGORN, a program to detect tRNA genes and tmRNA genes in nucleotide sequences. Nucleic Acids Res. 2004;32(1):11–6.
Kinouchi M, Kurokawa K. [Special issue: fact databases and freewares] tRNAfinder: a software system to find all tRNA genes in the DNA sequence based on the cloverleaf secondary structure. J Comput Aided Chem. 2006;7:116–24.
Overbeek R, Olson R, Pusch G, Olsen G, Davis J, Disz T, et al. The SEED and the rapid annotation of microbial genomes using subsystems technology (RAST). Nucleic Acids Res. 2013;42(D1):D206–14.
Seemann T. Prokka: rapid prokaryotic genome annotation. Bioinformatics. 2014;30(14):2068–9.
Zimin A, Marçais G, Puiu D, Roberts M, Salzberg S, Yorke J. The MaSuRCA genome assembler. Bioinformatics. 2013;29(21):2669–77.
Otto T, Dillon G, Degrave W, Berriman M. RATT: rapid annotation transfer tool. Nucleic Acids Res. 2011;39(9):e57.
Thiele I, Palsson B. A protocol for generating a high-quality genome-scale metabolic reconstruction. Nat Protoc. 2010;5(1):93–121.
The Uniprot Consortium: the universal protein knowledgebase. Nucleic Acids Res. 2017;45(D1):D158–D169.
Barthelmes J, Ebeling C, Chang A, Schomburg I, Schomburg D. BRENDA, AMENDA and FRENDA: the enzyme information system in 2007. Nucleic Acids Res. 2007;35(Database):D511–4.
Kanehisa M, Goto S, Hattori M, Aoki-Kinoshita K, Itoh M, Kawashima S, et al. From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res. 2006;34(90001):D354–7.
Heavner B, Price N. Transparency in metabolic network reconstruction enables scalable biological discovery. Curr Opin Biotechnol. 2015;34:105–9.
Oberhardt M, Puchalka J, Fryer K, Martins dos Santos V, Papin J. Genome-scale metabolic network analysis of the opportunistic pathogen Pseudomonas aeruginosa PAO1. J Bacteriol. 2008;190(8):2790–803.
Vital-Lopez F, Reifman J, Wallqvist A. Biofilm formation mechanisms of Pseudomonas aeruginosa predicted via genome-scale kinetic models of bacterial metabolism. PLoS Comput Biol. 2015;11(10):e1004452.
Bartell J, Blazier A, Yen P, Thøgersen J, Jelsbak L, Goldberg J, et al. Reconstruction of the metabolic network of Pseudomonas aeruginosa to interrogate virulence factor synthesis. Nat Commun. 2017;8:14631.
Moreno-Hagelsieb G, Latimer K. Choosing BLAST options for better detection of orthologs as reciprocal best hits. Bioinformatics. 2008;24(3):319–24.
Novichkov P, Kazakov A, Ravcheev D, Leyn S, Kovaleva G, Sutormin R, et al. RegPrecise 3.0 – a resource for genome-scale exploration of transcriptional regulation in bacteria. BMC Genomics. 2013;14(1):745.
Bailey T, Boden M, Buske F, Frith M, Grant C, Clementi L, et al. MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 2009;37.(Web Server:W202–8.
Hwang S, Kim C, Ji S, Go J, Kim H, Yang S, et al. Network-assisted investigation of virulence and antibiotic-resistance systems in Pseudomonas aeruginosa. Sci Rep. 2016;6(1):26223.
Jeong H, Mason S, Barabási A, Oltvai Z. Lethality and centrality in protein networks. Nature. 2001;411(6833):41–2.
Shannon P, Markiel A, Owen O, Nitin SB, Jonathan TW, Daniel R, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504.
Trindade dos Santos M, Nascimento A, Medeiros Filho F, Silva F. Modeling gene transcriptional regulation. Theor Appl Asp Syst Biol. 2018;27:27–39.
Carrera J, Estrela R, Luo J, Rai N, Tsoukalas A, Tagkopoulos I. An integrative, multi-scale, genome-wide model reveals the phenotypic landscape of Escherichia coli. Mol Syst Biol. 2014;10(7):735.
Goldberg A, Chew Y, Karr J. Toward scalable whole-cell modeling of human cells. Proceedings of the 2016 annual ACM Conference on SIGSIM Principles of Advanced Discrete Simulation – SIGSIM-PADS ‘16. 2016.
Covert M, Palsson B. Transcriptional regulation in constraints-based metabolic models of Escherichia coli. J Biol Chem. 2002;277(31):28058–64.
Karr J, Sanghvi J, Macklin D, Arora A, Covert M. WholeCellKB: model organism databases for comprehensive whole-cell models. Nucleic Acids Res. 2013;41(D1):D787–92.
Karr J, Phillips N, Covert M. WholeCellSimDB: a hybrid relational/HDF database for whole-cell model predictions. Database. 2014;2014:bau095.
Lee R, Karr J, Covert M. WholeCellViz: data visualization for whole-cell models. BMC Bioinf. 2013;14(1):253.
Waltemath D, Karr J, Bergmann F, Chelliah V, Hucka M, Krantz M, et al. Toward community standards and software for whole-cell modeling. IEEE Trans Biomed Eng. 2016;63(10):2007–14.
Ottino J. Engineering complex systems. Nature. 2004;427(6973):399.
Carothers C, Bauer D, Pearce S. ROSS: a high-performance, low-memory, modular time warp system. J Parallel Distrib Comput. 2002;62(11):1648–69.
Macklin D, Ruggero N, Covert M. The future of whole-cell modeling. Curr Opin Biotechnol. 2014;28:111–5.
Abreu R, Castro M, Silva F. Simulation step size analysis of a whole-cell computational model of bacteria. AIP Conf Proc. 2016;1790(1):100014.
Hansen J. GNU octave beginner’s guide. Birmingham: Packt Publishing; 2011.
McPhillie M, Cain R, Narramore S, Fishwick C, Simmons K. Computational methods to identify new antibacterial targets. Chem Biol Drug Des. 2015;85(1):22–9.
Pujol A, Mosca R, Farrés J, Aloy P. Unveiling the role of network and systems biology in drug discovery. Trends Pharmacol Sci. 2010;31(3):115–23.
Schadt E, Friend S, Shaywitz D. A network view of disease and compound screening. Nat Rev Drug Discov. 2009;8(4):286–95.
Xie L, Li J, Xie L, Bourne P. Drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP inhibitors. PLoS Comput Biol. 2009;5(5):e1000387.
Murabito E, Smallbone K, Swinton J, Westerhoff H, Steuer R. A probabilistic approach to identify putative drug targets in biochemical networks. J R Soc Interface. 2010;8(59):880–95.
Rienksma R, Suarez-Diez M, Spina L, Schaap P. Martins dos Santos V. Systems-level modeling of mycobacterial metabolism for the identification of new (multi-)drug targets. Semin Immunol. 2014;26(6):610–22.
Kozakov D, Hall D, Napoleon R, Yueh C, Whitty A, Vajda S. New frontiers in druggability. J Med Chem. 2015;58(23):9063–88.
Vashisht R, Bhat A, Kushwaha S, Bhardwaj A, Consortium O, Brahmachari S. Systems level mapping of metabolic complexity in Mycobacterium tuberculosis to identify high-value drug targets. J Transl Med. 2014;12(1):263–81.
Chaudhury S, Abdulhameed M, Singh N, Tawa G, D’haeseleer P, Zemla A, et al. Rapid countermeasure discovery against Francisella tularensis based on a metabolic network reconstruction. PLoS One. 2013;8(5):e63369.
Lewis N, Nagarajan H, Palsson B. Constraining the metabolic genotype–phenotype relationship using a phylogeny of in silico methods. Nat Rev Microbiol. 2012;10(4):291–305.
Becker S, Palsson B. Context-specific metabolic networks are consistent with experiments. PLoS Comput Biol. 2008;4(5):e1000082.
Shlomi T, Cabili M, Herrgård M, Palsson B, Ruppin E. Network-based prediction of human tissue-specific metabolism. Nat Biotechnol. 2008;26(9):1003–10.
Colijn C, Brandes A, Zucker J, Lun D, Weiner B, Farhat M, et al. Interpreting expression data with metabolic flux models: predicting Mycobacterium tuberculosis mycolic acid production. PLoS Comput Biol. 2009;5(8):e1000489.
Zur H, Ruppin E, Shlomi T. iMAT: an integrative metabolic analysis tool. Bioinformatics. 2010;26(24):3140–2.
Chandrasekaran S, Price N. Probabilistic integrative modeling of genome-scale metabolic and regulatory networks in Escherichia coli and Mycobacterium tuberculosis. Proc Natl Acad Sci. 2010;107(41):17845–50.
Brandes A, Lun D, Ip K, Zucker J, Colijn C, Weiner B, et al. Inferring carbon sources from gene expression profiles using metabolic flux models. PLoS One. 2012;7(5):e36947.
Ma S, Minch K, Rustad T, Hobbs S, Zhou S, Sherman D, et al. Integrated modeling of gene regulatory and metabolic networks in Mycobacterium tuberculosis. PLoS Comput Biol. 2015;11(11):e1004543.
Garay C, Dreyfuss J, Galagan J. Metabolic modeling predicts metabolite changes in Mycobacterium tuberculosis. BMC Syst Biol. 2015;9(1):57.
Toleman MA, Simm AM, Murphy TA, Gales AC, Biedenbach DJ, Jones RN, Walsh TR, Molecular characterization of SPM-1, a novel metallo-?-lactamase isolated in Latin America: report from the SENTRY antimicrobial surveillance programme. J Antimicrob Chemother. 2002;50(5):673–9.
Acknowledgment
This study was supported by fellowships from CAPES to FMF and from the Oswaldo Cruz Institute (https://pgbcs.ioc.fiocruz.br/) to TG. We also thank FAPERJ and CAPES for financial support.
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da Silva, F.A.B. et al. (2018). Computational Modeling of Multidrug-Resistant Bacteria. In: Alves Barbosa da Silva, F., Carels, N., Paes Silva Junior, F. (eds) Theoretical and Applied Aspects of Systems Biology. Computational Biology, vol 27. Springer, Cham. https://doi.org/10.1007/978-3-319-74974-7_11
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