Campos, Débora Leite;
Canales, Christian Shleider Carnero;
Demarqui, Fernanda Manaia;
Fernandes, Guilherme FS;
Dos Santos, Camila Gonçalves;
Prates, João Lucas B;
Da Silva, Ingrid Gracielle Martins;
... Pavan, Fernando Rogério; + view all
(2024)
Screening of novel narrow-spectrum benzofuroxan derivatives for the treatment of multidrug-resistant tuberculosis through in silico, in vitro, and in vivo approaches.
Frontiers in Microbiology
, 15
, Article 1487829. 10.3389/fmicb.2024.1487829.
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Abstract
Tuberculosis remains a serious global health threat, exacerbated by the rise of resistant strains. This study investigates the potential of two benzofuroxan (Bfx) derivatives, 5n and 5b, as targeted treatments for MDR-TB using in silico, in vitro, and in vivo methodologies. In vitro analyses showed that Bfx compounds have significant activity against Mtb H37Rv, with Bfx 5n standing out with a MIC90 of 0.09 ± 0.04 μM. Additionally, their efficacy against MDR and pre-XDR strains was superior compared to commercial drugs. These Bfx compounds have a narrow spectrum for mycobacteria, which helps avoid dysbiosis of the gut microbiota, and they also exhibit high selectivity and low toxicity. Synergism studies indicate that Bfx derivatives could be combined with rifampicin to enhance treatment efficacy and reduce its duration. Scanning electron microscopy revealed severe damage to the morphology of Mtb following treatment with Bfx 5n, showing significant distortions in the bacillary structures. Whole-genome sequencing of the 5n-resistant isolate suggests resistance mechanisms mediated by the Rv1855c gene, supported by in silico studies. In vivo studies showed that the 5n compound reduced the pulmonary load by 3.0 log10 CFU/mL, demonstrating superiority over rifampicin, which achieved a reduction of 1.23 log10 CFU/mL. In conclusion, Bfx derivatives, especially 5n, effectively address resistant infections caused by Mtb, suggesting they could be a solid foundation for future therapeutic developments against MDR-TB.
| Type: | Article |
|---|---|
| Title: | Screening of novel narrow-spectrum benzofuroxan derivatives for the treatment of multidrug-resistant tuberculosis through in silico, in vitro, and in vivo approaches |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fmicb.2024.1487829 |
| Publisher version: | http://dx.doi.org/10.3389/fmicb.2024.1487829 |
| Language: | English |
| Additional information: | Copyright © 2024 Campos, Canales, Demarqui, Fernandes, dos Santos, Prates, da Silva, Barros-Cordeiro, Báo, de Andrade, Abichabki, Zacharias, de Campos, dos Santos and Pavan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | Benzofuroxan, multidrug-resistant, tuberculosis, Rv1855c, Mycobacterium tuberculosis, narrow-spectrum |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10199729 |
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