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ORIGINAL RESEARCH article

Front. Microbiol.
Sec. Infectious Agents and Disease
Volume 15 - 2024 | doi: 10.3389/fmicb.2024.1487829

Screening of Novel Narrow-Spectrum Benzofuroxan Derivatives for the Treatment of Multidrug-Resistant Tuberculosis through In silico, In vitro, and In vivo approaches

Provisionally accepted
Fernando R. Pavan Fernando R. Pavan 1*Debora Campos Debora Campos 1Christian Canales Christian Canales 1Fernanda Manieri Fernanda Manieri 1Guilherme F. Fernandes Guilherme F. Fernandes 2Camila Santos Camila Santos 1João Prates João Prates 1Ingrid Silva Ingrid Silva 3Karine Cordeiro Karine Cordeiro 3Sônia N. Báo Sônia N. Báo 3Leonardo N. Andrade Leonardo N. Andrade 4Nathália Abichabki Nathália Abichabki 4Luisa Zacharias Luisa Zacharias 4Marli Campos Marli Campos 5Jean L. Dos Santos Jean L. Dos Santos 1
  • 1 São Paulo State University, São Paulo, Brazil
  • 2 University College London, London, England, United Kingdom
  • 3 University of Brasilia, Brasilia, Distrito Federal, Brazil
  • 4 University of São Paulo, São Paulo, Rio Grande do Sul, Brazil
  • 5 Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil

The final, formatted version of the article will be published soon.

    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.

    Keywords: Benzofuroxan, Multidrug-resistant, Tuberculosis, Rv1855c, Mycobacterium tuberculosis, narrow-spectrum

    Received: 28 Aug 2024; Accepted: 01 Oct 2024.

    Copyright: © 2024 Pavan, Campos, Canales, Manieri, Fernandes, Santos, Prates, Silva, Cordeiro, Báo, Andrade, Abichabki, Zacharias, Campos and Dos Santos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor 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.

    * Correspondence: Fernando R. Pavan, São Paulo State University, São Paulo, Brazil

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.