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dc.contributor.authorMobegi, Fredrick
dc.contributor.authorvan Hijum, S.A.F.T.
dc.contributor.authorBurghout, P.
dc.contributor.authorBootsma, H.J.
dc.contributor.authorde Vries, S.P.W.
dc.contributor.authorvan der Gaast-de Jongh, C.E.
dc.contributor.authorSimonetti, E.
dc.contributor.authorLangereis, J.D.
dc.contributor.authorHermans, P.W.M.
dc.contributor.authorde Jonge, M.I.
dc.contributor.authorZomer, A.
dc.date.accessioned2020-08-24T06:55:28Z
dc.date.available2020-08-24T06:55:28Z
dc.date.issued2014
dc.identifier.citationMobegi, F.M. and van Hijum, S.A.F.T. and Burghout, P. and Bootsma, H.J. and de Vries, S.P.W. and van der Gaast-de Jongh, C.E. and Simonetti, E. et al. 2014. From microbial gene essentiality to novel antimicrobial drug targets. BMC Genomics. 15 (1): Article No. 958.
dc.identifier.urihttp://hdl.handle.net/20.500.11937/80737
dc.identifier.doi10.1186/1471-2164-15-958
dc.description.abstract

Background: Bacterial respiratory tract infections, mainly caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are among the leading causes of global mortality and morbidity. Increased resistance of these pathogens to existing antibiotics necessitates the search for novel targets to develop potent antimicrobials.

Result: Here, we report a proof of concept study for the reliable identification of potential drug targets in these human respiratory pathogens by combining high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics. Approximately 20% of all genes in these three species were essential for growth and viability, including 128 essential and conserved genes, part of 47 metabolic pathways. By comparing these essential genes to the human genome, and a database of genes from commensal human gut microbiota, we identified and excluded potential drug targets in respiratory tract pathogens that will have off-target effects in the host, or disrupt the natural host microbiota. We propose 249 potential drug targets, 67 of which are targets for 75 FDA-approved antimicrobials and 35 other researched small molecule inhibitors. Two out of four selected novel targets were experimentally validated, proofing the concept.

Conclusion: Here we have pioneered an attempt in systematically combining the power of high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics to discover potential drug targets at genome-scale. By circumventing the time-consuming and expensive laboratory screens traditionally used to select potential drug targets, our approach provides an attractive alternative that could accelerate the much needed discovery of novel antimicrobials.

dc.languageEnglish
dc.publisherBMC
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectScience & Technology
dc.subjectLife Sciences & Biomedicine
dc.subjectBiotechnology & Applied Microbiology
dc.subjectGenetics & Heredity
dc.subjectFATTY-ACID BIOSYNTHESIS
dc.subjectSTREPTOCOCCUS-PNEUMONIAE
dc.subjectHAEMOPHILUS-INFLUENZAE
dc.subjectMORAXELLA-CATARRHALIS
dc.subjectCARBONIC-ANHYDRASE
dc.subjectGENOME
dc.subjectIDENTIFICATION
dc.subjectRESISTANCE
dc.subjectPATHWAY
dc.subjectGROWTH
dc.titleFrom microbial gene essentiality to novel antimicrobial drug targets
dc.typeJournal Article
dcterms.source.volume15
dcterms.source.number1
dcterms.source.issn1471-2164
dcterms.source.titleBMC Genomics
dc.date.updated2020-08-24T06:55:25Z
curtin.note

© 2014 Mobegi et al. Published in BMC Genomics. This article is published under the Open Access publishing model and distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/. Please refer to the licence to obtain terms for any further reuse or distribution of this work.

curtin.departmentSchool of Molecular and Life Sciences (MLS)
curtin.accessStatusOpen access
curtin.facultyFaculty of Science and Engineering
curtin.contributor.orcidMobegi, Fredrick [0000-0003-0554-9919]
curtin.contributor.researcheridMobegi, Fredrick [D-1058-2015]
curtin.identifier.article-numberARTN 958
dcterms.source.eissn1471-2164
curtin.contributor.scopusauthoridMobegi, Fredrick [56479121000]


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