Publication
Fast identification of off-target liabilities in early antibiotic discovery with Fourier-transform infrared spectroscopy
dc.contributor.author | Ribeiro Da Cunha, Bernardo | |
dc.contributor.author | Aleixo, Sandra M. | |
dc.contributor.author | Fonseca, Luís P. P. | |
dc.contributor.author | Calado, Cecília | |
dc.date.accessioned | 2021-09-17T12:33:33Z | |
dc.date.available | 2021-09-17T12:33:33Z | |
dc.date.issued | 2021-08 | |
dc.description | Este 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.description | Este 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.description | Este 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.abstract | Structural 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.version | info:eu-repo/semantics/publishedVersion | pt_PT |
dc.identifier.citation | CUNHA, 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.doi | 10.1002/bit.27915 | pt_PT |
dc.identifier.eissn | 1097-0290 | |
dc.identifier.uri | http://hdl.handle.net/10400.21/13742 | |
dc.language.iso | eng | pt_PT |
dc.peerreviewed | yes | pt_PT |
dc.publisher | Wiley | pt_PT |
dc.relation | IPL/2018/RENALPROG_ISEL | pt_PT |
dc.relation | Centre of Statistics and its Applications | |
dc.relation | IPL/2017/DrugsPlatf/ISEL | pt_PT |
dc.relation.publisherversion | https://onlinelibrary.wiley.com/doi/epdf/10.1002/bit.27915 | pt_PT |
dc.subject | Fourier-transform infrared spectroscopy (FTIR) | pt_PT |
dc.subject | High-throughput screening | pt_PT |
dc.subject | Machine learning | pt_PT |
dc.subject | Mechanism of action | pt_PT |
dc.subject | Off-target liabilities | pt_PT |
dc.title | Fast identification of off-target liabilities in early antibiotic discovery with Fourier-transform infrared spectroscopy | pt_PT |
dc.type | journal article | |
dspace.entity.type | Publication | |
oaire.awardTitle | Centre of Statistics and its Applications | |
oaire.awardURI | info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00006%2F2020/PT | |
oaire.citation.endPage | 4476 | pt_PT |
oaire.citation.issue | 11 | |
oaire.citation.startPage | 4465 | pt_PT |
oaire.citation.volume | 118 | |
oaire.fundingStream | 6817 - DCRRNI ID | |
person.familyName | Ribeiro da Cunha | |
person.familyName | Aleixo | |
person.familyName | P. Fonseca | |
person.familyName | Calado | |
person.givenName | Bernardo | |
person.givenName | Sandra | |
person.givenName | Luis | |
person.givenName | Cecília | |
person.identifier | 130332 | |
person.identifier.ciencia-id | EA1E-4BEA-A01E | |
person.identifier.ciencia-id | 951D-DF38-3397 | |
person.identifier.ciencia-id | 9418-E320-3177 | |
person.identifier.orcid | 0000-0002-0303-9416 | |
person.identifier.orcid | 0000-0003-1740-8371 | |
person.identifier.orcid | 0000-0001-8429-6977 | |
person.identifier.orcid | 0000-0002-5264-9755 | |
person.identifier.rid | P-6154-2017 | |
person.identifier.rid | A-4228-2013 | |
person.identifier.rid | E-2102-2014 | |
person.identifier.scopus-author-id | 57211629814 | |
person.identifier.scopus-author-id | 24829443600 | |
person.identifier.scopus-author-id | 55916288400 | |
person.identifier.scopus-author-id | 6603163260 | |
project.funder.identifier | http://doi.org/10.13039/501100001871 | |
project.funder.name | Fundação para a Ciência e a Tecnologia | |
rcaap.rights | closedAccess | pt_PT |
rcaap.type | article | pt_PT |
relation.isAuthorOfPublication | 810fc4c7-6c05-44a0-81e5-6cfdb3c2088a | |
relation.isAuthorOfPublication | c7cbebb9-e51f-4f99-92cd-4b3eee61c6c9 | |
relation.isAuthorOfPublication | 5c533551-5113-4c0a-93f1-9c50cbd796bc | |
relation.isAuthorOfPublication | e8577257-c64c-4481-9b2b-940fedb360cc | |
relation.isAuthorOfPublication.latestForDiscovery | c7cbebb9-e51f-4f99-92cd-4b3eee61c6c9 | |
relation.isProjectOfPublication | 56604007-ee11-4ff0-b18e-a9fe359e7db1 | |
relation.isProjectOfPublication.latestForDiscovery | 56604007-ee11-4ff0-b18e-a9fe359e7db1 |
Files
Original bundle
1 - 1 of 1
No Thumbnail Available
- Name:
- Fast identification_SMAleixo.pdf
- Size:
- 1.61 MB
- Format:
- Adobe Portable Document Format