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Advisor(s)
Abstract(s)
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.
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
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
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
Keywords
Antibiotic discovery Bacterial cytological profiling Chemical genetics High-throughput screening Mechanism-of-Action (MOA) Metabolomics Phenotypic screening Proteomics Transcriptomics Vibrational spectroscopy
Pedagogical Context
Citation
CUNHA, Bernardo Ribeiro da; [et al] – Technologies for high-throughput identification of antibiotic mechanism of action. Antibiotics. ISSN 2079-6382. Vol. 10, N.º 5 (2021), pp. 1-20
Publisher
MDPI