Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepacia
There is an urgent need for new antimicrobials to treat the opportunistic Gram-negative Burkholderia cenocepacia, which represents a problematic challenge for cystic fibrosis patients. Recently, a benzothiadiazole derivative, C109, was shown to be effective against the infections caused by B. cenoce...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-04-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2020.00562/full |
| _version_ | 1819226931552321536 |
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| author | Laurent R. Chiarelli Viola Camilla Scoffone Gabriele Trespidi Giulia Barbieri Olga Riabova Natalia Monakhova Alessio Porta Giulia Manina Giovanna Riccardi Vadim Makarov Silvia Buroni |
| author_facet | Laurent R. Chiarelli Viola Camilla Scoffone Gabriele Trespidi Giulia Barbieri Olga Riabova Natalia Monakhova Alessio Porta Giulia Manina Giovanna Riccardi Vadim Makarov Silvia Buroni |
| author_sort | Laurent R. Chiarelli |
| collection | DOAJ |
| description | There is an urgent need for new antimicrobials to treat the opportunistic Gram-negative Burkholderia cenocepacia, which represents a problematic challenge for cystic fibrosis patients. Recently, a benzothiadiazole derivative, C109, was shown to be effective against the infections caused by B. cenocepacia and other Gram-negative and-positive bacteria. C109 has a promising cellular target, the cell division protein FtsZ, and a recently developed PEGylated formulation make it an attractive molecule to counteract Burkholderia infections. However, the ability of efflux pumps to extrude it out of the cell represents a limitation for its use. Here, more than 50 derivatives of C109 were synthesized and tested against Gram-negative species and the Gram-positive Staphylococcus aureus. In addition, their activity was evaluated on the purified FtsZ protein. The chemical, metabolic and cellular stability of C109 has been assayed using different biological systems, including quantitative single-cell imaging. However, no further improvement on C109 was achieved, and the role of efflux in resistance was further confirmed. Also, a novel nitroreductase that can inactivate the compound was characterized, but it does not appear to play a role in natural resistance. All these data allowed a deep characterization of the compound, which will contribute to a further improvement of its properties. |
| first_indexed | 2024-12-23T10:33:20Z |
| format | Article |
| id | doaj.art-771a8688f6c042509aba8391a0500a4d |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-23T10:33:20Z |
| publishDate | 2020-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-771a8688f6c042509aba8391a0500a4d2022-12-21T17:50:22ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2020-04-011110.3389/fmicb.2020.00562531369Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepaciaLaurent R. Chiarelli0Viola Camilla Scoffone1Gabriele Trespidi2Giulia Barbieri3Olga Riabova4Natalia Monakhova5Alessio Porta6Giulia Manina7Giovanna Riccardi8Vadim Makarov9Silvia Buroni10Laboratory of Molecular Microbiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyLaboratory of Molecular Microbiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyLaboratory of Molecular Microbiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyLaboratory of Molecular Microbiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyFederal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences, Moscow, RussiaFederal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences, Moscow, RussiaOrganic Chemistry Section, Department of Chemistry, University of Pavia, Pavia, ItalyMicrobial Individuality and Infection Group, Cell Biology and Infection Department, Institut Pasteur, Paris, FranceLaboratory of Molecular Microbiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyFederal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences, Moscow, RussiaLaboratory of Molecular Microbiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyThere is an urgent need for new antimicrobials to treat the opportunistic Gram-negative Burkholderia cenocepacia, which represents a problematic challenge for cystic fibrosis patients. Recently, a benzothiadiazole derivative, C109, was shown to be effective against the infections caused by B. cenocepacia and other Gram-negative and-positive bacteria. C109 has a promising cellular target, the cell division protein FtsZ, and a recently developed PEGylated formulation make it an attractive molecule to counteract Burkholderia infections. However, the ability of efflux pumps to extrude it out of the cell represents a limitation for its use. Here, more than 50 derivatives of C109 were synthesized and tested against Gram-negative species and the Gram-positive Staphylococcus aureus. In addition, their activity was evaluated on the purified FtsZ protein. The chemical, metabolic and cellular stability of C109 has been assayed using different biological systems, including quantitative single-cell imaging. However, no further improvement on C109 was achieved, and the role of efflux in resistance was further confirmed. Also, a novel nitroreductase that can inactivate the compound was characterized, but it does not appear to play a role in natural resistance. All these data allowed a deep characterization of the compound, which will contribute to a further improvement of its properties.https://www.frontiersin.org/article/10.3389/fmicb.2020.00562/fullBurkholderia cenocepacianew antimicrobialsdrug resistancecell divisioncystic fibrosis |
| spellingShingle | Laurent R. Chiarelli Viola Camilla Scoffone Gabriele Trespidi Giulia Barbieri Olga Riabova Natalia Monakhova Alessio Porta Giulia Manina Giovanna Riccardi Vadim Makarov Silvia Buroni Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepacia Frontiers in Microbiology Burkholderia cenocepacia new antimicrobials drug resistance cell division cystic fibrosis |
| title | Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepacia |
| title_full | Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepacia |
| title_fullStr | Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepacia |
| title_full_unstemmed | Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepacia |
| title_short | Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepacia |
| title_sort | chemical metabolic and cellular characterization of a ftsz inhibitor effective against burkholderia cenocepacia |
| topic | Burkholderia cenocepacia new antimicrobials drug resistance cell division cystic fibrosis |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2020.00562/full |
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