AUTHOR=Campos Débora Leite , Canales Christian Shleider Carnero , Demarqui Fernanda Manaia , Fernandes Guilherme F. S. , dos Santos Camila Gonçalves , Prates João Lucas B. , da Silva Ingrid Gracielle Martins , Barros-Cordeiro Karine Brenda , Báo Sônia Nair , de Andrade Leonardo Neves , Abichabki Nathália , Zacharias Luísa Vieira , de Campos Marli Matiko Anraku , dos Santos Jean Leandro , Pavan Fernando Rogério 

TITLE=Screening of novel narrow-spectrum benzofuroxan derivatives for the treatment of multidrug-resistant tuberculosis through in silico, in vitro, and in vivo approaches

JOURNAL=Frontiers in Microbiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1487829

DOI=10.3389/fmicb.2024.1487829

ISSN=1664-302X

ABSTRACT=<p>Tuberculosis remains a serious global health threat, exacerbated by the rise of resistant strains. This study investigates the potential of two benzofuroxan (<italic>Bfx</italic>) derivatives, 5n and 5b, as targeted treatments for MDR-TB using <italic>in silico</italic>, <italic>in vitro</italic>, and <italic>in vivo</italic> methodologies. <italic>In vitro</italic> analyses showed that <italic>Bfx</italic> compounds have significant activity against <italic>Mtb</italic> H37Rv, with <italic>Bfx</italic> 5n standing out with a MIC<sub>90</sub> of 0.09 ± 0.04 μM. Additionally, their efficacy against MDR and pre-XDR strains was superior compared to commercial drugs. These <italic>Bfx</italic> 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 <italic>Bfx</italic> derivatives could be combined with rifampicin to enhance treatment efficacy and reduce its duration. Scanning electron microscopy revealed severe damage to the morphology of <italic>Mtb</italic> following treatment with <italic>Bfx</italic> 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 <italic>in silico</italic> studies. <italic>In vivo</italic> studies showed that the 5n compound reduced the pulmonary load by 3.0 log<sub>10</sub> CFU/mL, demonstrating superiority over rifampicin, which achieved a reduction of 1.23 log<sub>10</sub> CFU/mL. In conclusion, <italic>Bfx</italic> derivatives, especially 5n, effectively address resistant infections caused by <italic>Mtb</italic>, suggesting they could be a solid foundation for future therapeutic developments against MDR-TB.</p>