Repurposing miconazole and tamoxifen for the treatment of Mycobacterium abscessus complex infections through in silico chemogenomics approach
Abstract Drug repositioning is an alternative to overcome the complexity of the drug discovery and approval procedures for the treatment of Mycobacterium abscessus Complex (MABSC) infections that are increasing globally due to the emergency of antimicrobial resistance mechanisms. Here, an in silico chemogenomics approach was performed to compare the sequences from 4942 M. abscessus subsp. abscessus (M. abscessus) proteins with 5258 or 3473 therapeutic targets registered in the DrugBank or Therapeutic Target Database, respectively. This comparison identified 446 drugs or drug candidates whose targets were homologous to M. abscessus proteins. These identified drugs were considered potential inhibitors of MABSC (anti-MABSC activity). Further screening and inspection resulted in the selection of ezetimibe, furosemide, itraconazole, miconazole (MCZ), tamoxifen (TAM), and thiabendazole (THI) for experimental validation. Among them, MCZ and TAM showed minimum inhibitory concentrations (MIC) of 32 and 24 µg $ mL^{−1} $ against M. abscessus, respectively. For M. bolletii and M. massiliense strains, MCZ and TAM showed MICs of 16 and 24 µg $ mL^{−1} $, in this order. Subsequently, the antibacterial activity of MCZ was confirmed in vivo, indicating its potential to reduce the bacterial load in the lungs of infected mice. These results show that MCZ and TAM can serve as molecular scaffolds for the prospective hit-2-lead optimization of new analogs with greater potency, selectivity, and permeability..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:39 |
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| Enthalten in: |
World journal of microbiology & biotechnology - 39(2023), 10 vom: 09. Aug. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Anjos, Laura Raniere Borges dos [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
Antimicrobial activity |
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| Anmerkungen: |
© The Author(s), under exclusive licence to Springer Nature B.V. 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| doi: |
10.1007/s11274-023-03718-w |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Abstract Drug repositioning is an alternative to overcome the complexity of the drug discovery and approval procedures for the treatment of Mycobacterium abscessus Complex (MABSC) infections that are increasing globally due to the emergency of antimicrobial resistance mechanisms. Here, an in silico chemogenomics approach was performed to compare the sequences from 4942 M. abscessus subsp. abscessus (M. abscessus) proteins with 5258 or 3473 therapeutic targets registered in the DrugBank or Therapeutic Target Database, respectively. This comparison identified 446 drugs or drug candidates whose targets were homologous to M. abscessus proteins. These identified drugs were considered potential inhibitors of MABSC (anti-MABSC activity). Further screening and inspection resulted in the selection of ezetimibe, furosemide, itraconazole, miconazole (MCZ), tamoxifen (TAM), and thiabendazole (THI) for experimental validation. Among them, MCZ and TAM showed minimum inhibitory concentrations (MIC) of 32 and 24 µg $ mL^{−1} $ against M. abscessus, respectively. For M. bolletii and M. massiliense strains, MCZ and TAM showed MICs of 16 and 24 µg $ mL^{−1} $, in this order. Subsequently, the antibacterial activity of MCZ was confirmed in vivo, indicating its potential to reduce the bacterial load in the lungs of infected mice. These results show that MCZ and TAM can serve as molecular scaffolds for the prospective hit-2-lead optimization of new analogs with greater potency, selectivity, and permeability. | ||
| 650 | 4 | |a Antimicrobial activity | |
| 650 | 4 | |a Chemogenomics | |
| 650 | 4 | |a Drug repositioning | |
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| 700 | 1 | |a Costa, Vinícius Alexandre Fiaia |0 (orcid)0000-0001-6479-5963 |4 aut | |
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| 700 | 1 | |a Junqueira-Kipnis, Ana Paula |0 (orcid)0000-0002-4200-6617 |4 aut | |
| 700 | 1 | |a Kipnis, André |0 (orcid)0000-0001-5950-106X |4 aut | |
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