{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T06:34:36Z","timestamp":1781073276974,"version":"3.54.1"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"20","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: Synthetic lethal sets are sets of reactions\/genes where only the simultaneous removal of all reactions\/genes in the set abolishes growth of an organism. Previous approaches to identify synthetic lethal genes in genome-scale metabolic networks have built on the framework of flux balance analysis (FBA), extending it either to exhaustively analyze all possible combinations of genes or formulate the problem as a bi-level mixed integer linear programming (MILP) problem. We here propose an algorithm, Fast-SL, which surmounts the computational complexity of previous approaches by iteratively reducing the search space for synthetic lethals, resulting in a substantial reduction in running time, even for higher order synthetic lethals.<\/jats:p>\n               <jats:p>Results: We performed synthetic reaction and gene lethality analysis, using Fast-SL, for genome-scale metabolic networks of Escherichia coli, Salmonella enterica Typhimurium and Mycobacterium tuberculosis. Fast-SL also rigorously identifies synthetic lethal gene deletions, uncovering synthetic lethal triplets that were not reported previously. We confirm that the triple lethal gene sets obtained for the three organisms have a precise match with the results obtained through exhaustive enumeration of lethals performed on a computer cluster. We also parallelized our algorithm, enabling the identification of synthetic lethal gene quadruplets for all three organisms in under 6\u2009h. Overall, Fast-SL enables an efficient enumeration of higher order synthetic lethals in metabolic networks, which may help uncover previously unknown genetic interactions and combinatorial drug targets.<\/jats:p>\n               <jats:p>Availability and implementation: The MATLAB implementation of the algorithm, compatible with COBRA toolbox v2.0, is available at https:\/\/github.com\/RamanLab\/FastSL<\/jats:p>\n               <jats:p>Contact: \u00a0kraman@iitm.ac.in<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btv352","type":"journal-article","created":{"date-parts":[[2015,6,18]],"date-time":"2015-06-18T02:35:39Z","timestamp":1434594939000},"page":"3299-3305","source":"Crossref","is-referenced-by-count":62,"title":["Fast-SL: an efficient algorithm to identify synthetic lethal sets in metabolic networks"],"prefix":"10.1093","volume":"31","author":[{"given":"Aditya","family":"Pratapa","sequence":"first","affiliation":[{"name":"1 Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shankar","family":"Balachandran","sequence":"additional","affiliation":[{"name":"2 Department of Computer Science and Engineering, Indian Institute of Technology Madras, Chennai 600\u2009036, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik","family":"Raman","sequence":"additional","affiliation":[{"name":"1 Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,6,17]]},"reference":[{"key":"2023020202313564900_btv352-B1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.biosystems.2008.06.015","article-title":"Modes and cuts in metabolic networks: complexity and algorithms","volume":"95","author":"Acu\u00f1a","year":"2009","journal-title":"Biosystems"},{"key":"2023020202313564900_btv352-B2","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ymben.2004.12.003","article-title":"Identifying gene targets for the metabolic engineering of lycopene biosynthesis in Escherichia coli","volume":"7","author":"Alper","year":"2005","journal-title":"Metab. Eng."},{"key":"2023020202313564900_btv352-B3","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.jtbi.2007.09.043","article-title":"Structural robustness of metabolic networks with respect to multiple knockouts","volume":"252","author":"Behre","year":"2008","journal-title":"J. Theor. Biol."},{"key":"2023020202313564900_btv352-B4","doi-asserted-by":"crossref","first-page":"4893","DOI":"10.1038\/ncomms5893","article-title":"An exact arithmetic toolbox for a consistent and reproducible structural analysis of metabolic network models","volume":"5","author":"Chindelevitch","year":"2014","journal-title":"Nature Commun."},{"key":"2023020202313564900_btv352-B5","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/ng1856","article-title":"Multiple knockout analysis of genetic robustness in the yeast metabolic network","volume":"38","author":"Deutscher","year":"2006","journal-title":"Nat. Genet."},{"key":"2023020202313564900_btv352-B6","first-page":"50","article-title":"Can single knockouts accurately single out gene functions? BMC Syst","volume":"2","author":"Deutscher","year":"2008","journal-title":"Biol."},{"key":"2023020202313564900_btv352-B7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2105-1-1","article-title":"Metabolic flux balance analysis and the in silico analysis of Escherichia coli K-12 gene deletions","volume":"1","author":"Edwards","year":"2000","journal-title":"BMC Bioinformatics"},{"key":"2023020202313564900_btv352-B8","doi-asserted-by":"crossref","first-page":"13134","DOI":"10.1073\/pnas.2235812100","article-title":"Saccharomyces cerevisiae phenotypes can be predicted by using constraint-based analysis of a genome-scale reconstructed metabolic network","volume":"100","author":"Famili","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"2023020202313564900_btv352-B9","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/1752-0509-4-160","article-title":"Development and analysis of an in\u00a0vivo-compatible metabolic network of Mycobacterium tuberculosis","volume":"4","author":"Fang","year":"2010","journal-title":"BMC Syst. Biol."},{"key":"2023020202313564900_btv352-B10","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/msb4100155","article-title":"A genome-scale metabolic reconstruction for Escherichia coli K-12 MG1655 that accounts for 1260 ORFs and thermodynamic information","volume":"3","author":"Feist","year":"2007","journal-title":"Mol. Syst. Biol."},{"key":"2023020202313564900_btv352-B11","doi-asserted-by":"crossref","first-page":"e1003637","DOI":"10.1371\/journal.pcbi.1003637","article-title":"Essential plasticity and redundancy of metabolism unveiled by synthetic lethality analysis","volume":"10","author":"G\u00fcell","year":"2014","journal-title":"PLoS Comput. Biol."},{"key":"2023020202313564900_btv352-B12","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1073\/pnas.0607153104","article-title":"Plasticity of genetic interactions in metabolic networks of yeast","volume":"104","author":"Harrison","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"2023020202313564900_btv352-B13","doi-asserted-by":"crossref","DOI":"10.1099\/mic.0.076091-0","article-title":"Identification of potential drug targets in Salmonella enterica sv. Typhimurium using metabolic modelling and experimental validation","author":"Hartman","year":"2014","journal-title":"Microbiology"},{"key":"2023020202313564900_btv352-B14","first-page":"012025","article-title":"Application of high-performance computing to the reconstruction, analysis, and optimization of genome-scale metabolic models","volume":"180","author":"Henry","year":"2009","journal-title":"J. Phys.: Conf. Ser."},{"key":"2023020202313564900_btv352-B15","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1752-0509-1-26","article-title":"Investigating the metabolic capabilities of Mycobacterium tuberculosis H37Rv using the in silico strain iNJ661 and proposing alternative drug targets","volume":"1","author":"Jamshidi","year":"2007","journal-title":"BMC Syst. Biol."},{"key":"2023020202313564900_btv352-B16","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.copbio.2003.08.001","article-title":"Advances in flux balance analysis","volume":"14","author":"Kauffman","year":"2003","journal-title":"Curr. Opin. Biotechnol."},{"key":"2023020202313564900_btv352-B17","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/msb.2010.115","article-title":"Integrative genome-scale metabolic analysis of Vibrio vulnificus for drug targeting and discovery","volume":"7","author":"Kim","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"2023020202313564900_btv352-B18","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1101\/gr.3992505","article-title":"Metabolic functions of duplicate genes in Saccharomyces cerevisiae","volume":"12","author":"Kuepfer","year":"2005","journal-title":"Genome Res."},{"key":"2023020202313564900_btv352-B19","doi-asserted-by":"crossref","first-page":"4015","DOI":"10.1128\/JB.01743-08","article-title":"Comparative genome-scale metabolic reconstruction and flux balance analysis of multiple Staphylococcus aureus genomes identify novel antimicrobial drug targets","volume":"191","author":"Lee","year":"2009","journal-title":"J. Bacteriol."},{"key":"2023020202313564900_btv352-B20","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1093\/bfgp\/elr034","article-title":"Applications of system-level models of metabolism for analysis of bacterial physiology and identification of new drug targets","volume":"10","author":"Navid","year":"2011","journal-title":"Brief. Funct. Genomics."},{"key":"2023020202313564900_btv352-B21","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.pt.2007.08.013","article-title":"Metabolic reconstruction and analysis for parasite genomes","volume":"23","author":"Pinney","year":"2007","journal-title":"Trends Parasitol."},{"key":"2023020202313564900_btv352-B22","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1038\/msb.2010.60","article-title":"Reconstruction and flux-balance analysis of the Plasmodium falciparum metabolic network","volume":"6","author":"Plata","year":"2010","journal-title":"Mol. Syst. Biol."},{"key":"2023020202313564900_btv352-B23","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1752-0509-3-38","article-title":"Constraint-based analysis of metabolic capacity of Salmonella typhimurium during host-pathogen interaction","volume":"3","author":"Raghunathan","year":"2009","journal-title":"BMC Syst. Biol."},{"key":"2023020202313564900_btv352-B24","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1038\/nprot.2011.308","article-title":"Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox v2.0","volume":"6","author":"Schellenberger","year":"2011","journal-title":"Nat. Protoc."},{"key":"2023020202313564900_btv352-B25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0034337","article-title":"A systems biology approach to drug targets in Pseudomonas aeruginosa biofilm","volume":"7","author":"Sigurdsson","year":"2012","journal-title":"PLoS One"},{"key":"2023020202313564900_btv352-B26","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/msb.2009.56","article-title":"Genome-scale gene\/reaction essentiality and synthetic lethality analysis","volume":"5","author":"Suthers","year":"2009","journal-title":"Mol. Syst. Biol."},{"key":"2023020202313564900_btv352-B27","doi-asserted-by":"crossref","first-page":"5818","DOI":"10.1128\/JB.187.16.5818-5830.2005","article-title":"Expanded metabolic reconstruction of Helicobacter pylori (iIT341 GSM\/GPR): an in silico genome-scale characterization of single- and double-deletion mutants","volume":"187","author":"Thiele","year":"2005","journal-title":"J. Bacteriol."},{"key":"2023020202313564900_btv352-B28","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1752-0509-5-8","article-title":"A community effort towards a knowledge-base and mathematical model of the human pathogen Salmonella Typhimurium LT2","volume":"5","author":"Thiele","year":"2011","journal-title":"BMC Syst. Biol."},{"key":"2023020202313564900_btv352-B29","doi-asserted-by":"crossref","first-page":"3724","DOI":"10.1128\/aem.60.10.3724-3731.1994","article-title":"Stoichiometric flux balance models quantitatively predict growth and metabolic by-product secretion in wild-type Escherichia coli W3110","volume":"60","author":"Varma","year":"1994","journal-title":"Appl. Environ. Microb."},{"key":"2023020202313564900_btv352-B30","doi-asserted-by":"crossref","first-page":"e1003378","DOI":"10.1371\/journal.pcbi.1003378","article-title":"Enumeration of smallest intervention strategies in genome-scale metabolic networks","volume":"10","author":"von Kamp","year":"2014","journal-title":"PLoS Comput. Biol."},{"key":"2023020202313564900_btv352-B31","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/msb.2013.6","article-title":"Dissecting the energy metabolism in Mycoplasma pneumoniae through genome-scale metabolic modeling","volume":"9","author":"Wodke","year":"2013","journal-title":"Mol. Syst. Biol."},{"key":"2023020202313564900_btv352-B32","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1093\/bioinformatics\/btv134","article-title":"Logical transformation of genome scale metabolic models for gene level applications and analysis","volume":"31","author":"Zhang","year":"2015","journal-title":"Bioinformatics"},{"key":"2023020202313564900_btv352-B33","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.drudis.2006.11.008","article-title":"Multi-target therapeutics: when the whole is greater than the sum of the parts","volume":"12","author":"Zimmermann","year":"2007","journal-title":"Drug Discov. Today"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/31\/20\/3299\/49035819\/bioinformatics_31_20_3299.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/31\/20\/3299\/49035819\/bioinformatics_31_20_3299.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T03:50:34Z","timestamp":1675309834000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/31\/20\/3299\/195638"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,6,17]]},"references-count":33,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2015,10,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btv352","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2015,10,15]]},"published":{"date-parts":[[2015,6,17]]}}}