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Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections
Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of M. tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413995/ https://www.ncbi.nlm.nih.gov/pubmed/36015139 http://dx.doi.org/10.3390/ph15080992 |
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author | Mori, Matteo Stelitano, Giovanni Griego, Anna Chiarelli, Laurent R. Cazzaniga, Giulia Gelain, Arianna Pini, Elena Camera, Marina Canzano, Paola Fumagalli, Andrea Scarpa, Edoardo Cordiglieri, Chiara Rizzello, Loris Villa, Stefania Meneghetti, Fiorella |
author_facet | Mori, Matteo Stelitano, Giovanni Griego, Anna Chiarelli, Laurent R. Cazzaniga, Giulia Gelain, Arianna Pini, Elena Camera, Marina Canzano, Paola Fumagalli, Andrea Scarpa, Edoardo Cordiglieri, Chiara Rizzello, Loris Villa, Stefania Meneghetti, Fiorella |
author_sort | Mori, Matteo |
collection | PubMed |
description | Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of M. tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new anti-TB agents is the salicylate synthase MbtI, the first enzyme of the mycobacterial siderophore biochemical machinery, absent in human cells. In this work, a set of analogues of 5-(3-cyanophenyl)furan-2-carboxylic acid (I), the most potent MbtI inhibitor identified to date, was synthesized, characterized, and tested to further elucidate the structural requirements for achieving an efficient MbtI inhibition and potent antitubercular activity. The structure–activity relationships (SAR) discussed herein evidenced the importance of the side chain linked to the phenyl moiety to improve the in vitro antimycobacterial activity. In detail, 1f emerged as the most effective analogue against the pathogen, acting without cytotoxicity issues. To deepen the understanding of its mechanism of action, we established a fluorescence-based screening test to quantify the pathogen infectivity within host cells, using MPI-2 murine cells, a robust surrogate for alveolar macrophages. The set-up of the new assay demonstrates significant potential to accelerate the discovery of new anti-TB drugs. |
format | Online Article Text |
id | pubmed-9413995 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94139952022-08-27 Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections Mori, Matteo Stelitano, Giovanni Griego, Anna Chiarelli, Laurent R. Cazzaniga, Giulia Gelain, Arianna Pini, Elena Camera, Marina Canzano, Paola Fumagalli, Andrea Scarpa, Edoardo Cordiglieri, Chiara Rizzello, Loris Villa, Stefania Meneghetti, Fiorella Pharmaceuticals (Basel) Article Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of M. tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new anti-TB agents is the salicylate synthase MbtI, the first enzyme of the mycobacterial siderophore biochemical machinery, absent in human cells. In this work, a set of analogues of 5-(3-cyanophenyl)furan-2-carboxylic acid (I), the most potent MbtI inhibitor identified to date, was synthesized, characterized, and tested to further elucidate the structural requirements for achieving an efficient MbtI inhibition and potent antitubercular activity. The structure–activity relationships (SAR) discussed herein evidenced the importance of the side chain linked to the phenyl moiety to improve the in vitro antimycobacterial activity. In detail, 1f emerged as the most effective analogue against the pathogen, acting without cytotoxicity issues. To deepen the understanding of its mechanism of action, we established a fluorescence-based screening test to quantify the pathogen infectivity within host cells, using MPI-2 murine cells, a robust surrogate for alveolar macrophages. The set-up of the new assay demonstrates significant potential to accelerate the discovery of new anti-TB drugs. MDPI 2022-08-11 /pmc/articles/PMC9413995/ /pubmed/36015139 http://dx.doi.org/10.3390/ph15080992 Text en © 2022 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 | Article Mori, Matteo Stelitano, Giovanni Griego, Anna Chiarelli, Laurent R. Cazzaniga, Giulia Gelain, Arianna Pini, Elena Camera, Marina Canzano, Paola Fumagalli, Andrea Scarpa, Edoardo Cordiglieri, Chiara Rizzello, Loris Villa, Stefania Meneghetti, Fiorella Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections |
title | Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections |
title_full | Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections |
title_fullStr | Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections |
title_full_unstemmed | Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections |
title_short | Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections |
title_sort | synthesis and assessment of the in vitro and ex vivo activity of salicylate synthase (mbti) inhibitors as new candidates for the treatment of mycobacterial infections |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413995/ https://www.ncbi.nlm.nih.gov/pubmed/36015139 http://dx.doi.org/10.3390/ph15080992 |
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