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<p>Chordate mammalian models are widely used in preclinical infectious disease research but have limitations, driving the search for viable alternatives. Among emerging models, zebrafish (<i>Danio rerio</i>) stands out due to its genetic similarity to humans and a well-developed immune system. This study proposes an <i>in vivo</i> zebrafish infection model to evaluate treatments against antibiotic-resistant <i>Staphylococcus aureus</i>, focusing on inhibiting the NorA efflux pump. The strains SA 1199 (wild-type) and 1199B (mutant), both carrying NorA, were used. <i>In vitro</i> assays determined the Minimum Inhibitory Concentration (MIC) of norfloxacin and chlorpromazine (a standard efflux pump inhibitor) via serial broth microdilution. For <i>in vivo</i> assays, anesthetized adult fish were dorsally infected (10⁸ CFU/mL) and treated 24&#xa0;h later with norfloxacin alone or combined with chlorpromazine. After 24&#xa0;h, fish were euthanized, muscles dissected, homogenized, and plated for CFU counting. The infection model was effective, with control fish showing 1.6 × 10⁶ CFU/mL (SA 1199) and 1.8 × 10⁶ CFU/mL (SA 1199B). Norfloxacin at MIC did not reduce CFU counts, but its combination with chlorpromazine at a subinhibitory concentration successfully reduced infection in both strains. Infected fish developed hypopigmented muscle lesions, possibly due to decreased melanophore melanin production. These findings validate <i>D. rerio</i> as a viable <i>in vivo</i> model for studying NorA efflux pump inhibitors in <i>S. aureus</i>, reinforcing its potential for researching novel therapies against antibiotic-resistant infections.</p>

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Establishing a Zebrafish (Danio rerio) infection model to assess antimicrobial treatment efficacy against Staphylococcus aureus expressing the NorA efflux pump

  • 期刊论文

  • 发表日期：

    2026年2月6日

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  • José Weverton Almeida-Bezerra,
  • Gabriel Gonçalves Alencar,
  • Lucas Yure Santos da Silva,
  • Janaína Esmeraldo Rocha,
  • Francisco Nascimento Pereira Junior,
  • Anita Oliveira Brito Pereira Bezerra Martins,
  • Saulo Almeida Menezes,
  • Irwin Rose Alencar de Menezes,
  • Maria Flaviana Bezerra Morais-Braga,
  • Edinardo Fagner Ferreira Matias,
  • Henrique Douglas Melo Coutinho

摘要

Chordate mammalian models are widely used in preclinical infectious disease research but have limitations, driving the search for viable alternatives. Among emerging models, zebrafish (Danio rerio) stands out due to its genetic similarity to humans and a well-developed immune system. This study proposes an in vivo zebrafish infection model to evaluate treatments against antibiotic-resistant Staphylococcus aureus, focusing on inhibiting the NorA efflux pump. The strains SA 1199 (wild-type) and 1199B (mutant), both carrying NorA, were used. In vitro assays determined the Minimum Inhibitory Concentration (MIC) of norfloxacin and chlorpromazine (a standard efflux pump inhibitor) via serial broth microdilution. For in vivo assays, anesthetized adult fish were dorsally infected (10⁸ CFU/mL) and treated 24 h later with norfloxacin alone or combined with chlorpromazine. After 24 h, fish were euthanized, muscles dissected, homogenized, and plated for CFU counting. The infection model was effective, with control fish showing 1.6 × 10⁶ CFU/mL (SA 1199) and 1.8 × 10⁶ CFU/mL (SA 1199B). Norfloxacin at MIC did not reduce CFU counts, but its combination with chlorpromazine at a subinhibitory concentration successfully reduced infection in both strains. Infected fish developed hypopigmented muscle lesions, possibly due to decreased melanophore melanin production. These findings validate D. rerio as a viable in vivo model for studying NorA efflux pump inhibitors in S. aureus, reinforcing its potential for researching novel therapies against antibiotic-resistant infections.