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Technologies for High-Throughput Identification of Antibiotic Mechanism of Action
There are two main strategies for antibiotic discovery: target-based and phenotypic screening. The latter has been much more successful in delivering first-in-class antibiotics, despite the major bottleneck of delayed Mechanism-of-Action (MOA) identification. Although finding new antimicrobial compo...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151116/ https://www.ncbi.nlm.nih.gov/pubmed/34065815 http://dx.doi.org/10.3390/antibiotics10050565 |
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author | da Cunha, Bernardo Ribeiro Zoio, Paulo Fonseca, Luís P. Calado, Cecília R. C. |
author_facet | da Cunha, Bernardo Ribeiro Zoio, Paulo Fonseca, Luís P. Calado, Cecília R. C. |
author_sort | da Cunha, Bernardo Ribeiro |
collection | PubMed |
description | There are two main strategies for antibiotic discovery: target-based and phenotypic screening. The latter has been much more successful in delivering first-in-class antibiotics, despite the major bottleneck of delayed Mechanism-of-Action (MOA) identification. Although finding new antimicrobial compounds is a very challenging task, identifying their MOA has proven equally challenging. MOA identification is important because it is a great facilitator of lead optimization and improves the chances of commercialization. Moreover, the ability to rapidly detect MOA could enable a shift from an activity-based discovery paradigm towards a mechanism-based approach. This would allow to probe the grey chemical matter, an underexplored source of structural novelty. In this study we review techniques with throughput suitable to screen large libraries and sufficient sensitivity to distinguish MOA. In particular, the techniques used in chemical genetics (e.g., based on overexpression and knockout/knockdown collections), promoter-reporter libraries, transcriptomics (e.g., using microarrays and RNA sequencing), proteomics (e.g., either gel-based or gel-free techniques), metabolomics (e.g., resourcing to nuclear magnetic resonance or mass spectrometry techniques), bacterial cytological profiling, and vibrational spectroscopy (e.g., Fourier-transform infrared or Raman scattering spectroscopy) were discussed. Ultimately, new and reinvigorated phenotypic assays bring renewed hope in the discovery of a new generation of antibiotics. |
format | Online Article Text |
id | pubmed-8151116 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81511162021-05-27 Technologies for High-Throughput Identification of Antibiotic Mechanism of Action da Cunha, Bernardo Ribeiro Zoio, Paulo Fonseca, Luís P. Calado, Cecília R. C. Antibiotics (Basel) Review There are two main strategies for antibiotic discovery: target-based and phenotypic screening. The latter has been much more successful in delivering first-in-class antibiotics, despite the major bottleneck of delayed Mechanism-of-Action (MOA) identification. Although finding new antimicrobial compounds is a very challenging task, identifying their MOA has proven equally challenging. MOA identification is important because it is a great facilitator of lead optimization and improves the chances of commercialization. Moreover, the ability to rapidly detect MOA could enable a shift from an activity-based discovery paradigm towards a mechanism-based approach. This would allow to probe the grey chemical matter, an underexplored source of structural novelty. In this study we review techniques with throughput suitable to screen large libraries and sufficient sensitivity to distinguish MOA. In particular, the techniques used in chemical genetics (e.g., based on overexpression and knockout/knockdown collections), promoter-reporter libraries, transcriptomics (e.g., using microarrays and RNA sequencing), proteomics (e.g., either gel-based or gel-free techniques), metabolomics (e.g., resourcing to nuclear magnetic resonance or mass spectrometry techniques), bacterial cytological profiling, and vibrational spectroscopy (e.g., Fourier-transform infrared or Raman scattering spectroscopy) were discussed. Ultimately, new and reinvigorated phenotypic assays bring renewed hope in the discovery of a new generation of antibiotics. MDPI 2021-05-12 /pmc/articles/PMC8151116/ /pubmed/34065815 http://dx.doi.org/10.3390/antibiotics10050565 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review da Cunha, Bernardo Ribeiro Zoio, Paulo Fonseca, Luís P. Calado, Cecília R. C. Technologies for High-Throughput Identification of Antibiotic Mechanism of Action |
title | Technologies for High-Throughput Identification of Antibiotic Mechanism of Action |
title_full | Technologies for High-Throughput Identification of Antibiotic Mechanism of Action |
title_fullStr | Technologies for High-Throughput Identification of Antibiotic Mechanism of Action |
title_full_unstemmed | Technologies for High-Throughput Identification of Antibiotic Mechanism of Action |
title_short | Technologies for High-Throughput Identification of Antibiotic Mechanism of Action |
title_sort | technologies for high-throughput identification of antibiotic mechanism of action |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151116/ https://www.ncbi.nlm.nih.gov/pubmed/34065815 http://dx.doi.org/10.3390/antibiotics10050565 |
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