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Fast identification of off-target liabilities in early antibiotic discovery with Fourier-transform infrared spectroscopy

dc.contributor.authorRibeiro Da Cunha, Bernardo
dc.contributor.authorAleixo, Sandra M.
dc.contributor.authorFonseca, Luís P. P.
dc.contributor.authorCalado, Cecília
dc.date.accessioned2021-09-17T12:33:33Z
dc.date.available2021-09-17T12:33:33Z
dc.date.issued2021-08
dc.descriptionEste trabalho foi financiado pelo Concurso Anual para Projetos de Investigação, Desenvolvimento, Inovação e Criação Artística (IDI&CA) 2018 do Instituto Politécnico de Lisboa. Código de referência IPL/2018/RENALPROG_ISEL
dc.descriptionEste trabalho foi financiado pelo Concurso Anual para Projetos de Investigação, Desenvolvimento, Inovação e Criação Artística (IDI&CA) 2020 do Instituto Politécnico de Lisboa. Código de referência IPL/2020/NephroMD/ISEL
dc.descriptionEste trabalho foi financiado pelo Concurso Anual para Projetos de Investigação, Desenvolvimento, Inovação e Criação Artística (IDI&CA) 2017 do Instituto Politécnico de Lisboa. Código de referência IPL/2017/DrugsPlatf/ISEL
dc.description.abstractStructural modifications of known antibiotic scaffolds have kept the upper hand on resistance, but we are on the verge of not having antibiotics for many common infections. Mechanism-based discovery assays reveal novelty, exclude off-target liabilities, and guide lead optimization. For that, we developed a fast and automatable protocol using high-throughput Fourier-transform infrared spectroscopy (FTIRS). Metabolic fingerprints of Staphylococcus aureus and Escherichia coli exposed to 35 compounds, dissolved in dimethyl sulfoxide (DMSO) or water, were acquired. Our data analysis pipeline identified biomarkers of off-target effects, optimized spectral preprocessing, and identified the top-performing machine learning algorithms for off-target liabilities and mechanism of action (MOA) identification. Spectral bands with known biochemical associations more often yielded more significant biomarkers of off-target liabilities when bacteria were exposed to compounds dissolved in water than DMSO. Highly discriminative models distinguished compounds with predominant off-target effects from antibiotics with well-defined MOA (AUROC > 0.87, AUPR > 0.79, F1 > 0.81), and from the latter predicted their MOA (AUROC > 0.88, AUPR > 0.70, F1 > 0.70). The compound solvent did not affect predictive models. FTIRS is fast, simple, inexpensive, automatable, and highly effective at predicting MOA and off-target liabilities. As such, FTIRS mechanism-based screening assays can be applied for hit discovery and to guide lead optimization during the early stages of antibiotic discovery.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCUNHA, Bernardo Ribeiro da; [et al] – Fast identification of off-target liabilities in early antibiotic discovery with Fourier-transform infrared spectroscopy. Biotechnology and Bioengineering. ISSN 1097-0290. Vol. 118, N.º 11 (2021), pp. 4465-4476.pt_PT
dc.identifier.doi10.1002/bit.27915pt_PT
dc.identifier.eissn1097-0290
dc.identifier.urihttp://hdl.handle.net/10400.21/13742
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relationIPL/2018/RENALPROG_ISELpt_PT
dc.relationCentre of Statistics and its Applications
dc.relationIPL/2017/DrugsPlatf/ISELpt_PT
dc.relation.publisherversionhttps://onlinelibrary.wiley.com/doi/epdf/10.1002/bit.27915pt_PT
dc.subjectFourier-transform infrared spectroscopy (FTIR)pt_PT
dc.subjectHigh-throughput screeningpt_PT
dc.subjectMachine learningpt_PT
dc.subjectMechanism of actionpt_PT
dc.subjectOff-target liabilitiespt_PT
dc.titleFast identification of off-target liabilities in early antibiotic discovery with Fourier-transform infrared spectroscopypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCentre of Statistics and its Applications
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00006%2F2020/PT
oaire.citation.endPage4476pt_PT
oaire.citation.issue11
oaire.citation.startPage4465pt_PT
oaire.citation.volume118
oaire.fundingStream6817 - DCRRNI ID
person.familyNameRibeiro da Cunha
person.familyNameAleixo
person.familyNameP. Fonseca
person.familyNameCalado
person.givenNameBernardo
person.givenNameSandra
person.givenNameLuis
person.givenNameCecília
person.identifier130332
person.identifier.ciencia-idEA1E-4BEA-A01E
person.identifier.ciencia-id951D-DF38-3397
person.identifier.ciencia-id9418-E320-3177
person.identifier.orcid0000-0002-0303-9416
person.identifier.orcid0000-0003-1740-8371
person.identifier.orcid0000-0001-8429-6977
person.identifier.orcid0000-0002-5264-9755
person.identifier.ridP-6154-2017
person.identifier.ridA-4228-2013
person.identifier.ridE-2102-2014
person.identifier.scopus-author-id57211629814
person.identifier.scopus-author-id24829443600
person.identifier.scopus-author-id55916288400
person.identifier.scopus-author-id6603163260
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsclosedAccesspt_PT
rcaap.typearticlept_PT
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