Treatment of severe pneumonia by hinokitiol in a murine antimicrobial-resistant pneumococcal pneumonia model

PLoS One. 2020 Oct 15;15(10):e0240329. doi: 10.1371/journal.pone.0240329. eCollection 2020.

Abstract

Streptococcus pneumoniae is often isolated from patients with community-acquired pneumonia. Antibiotics are the primary line of treatment for pneumococcal pneumonia; however, rising antimicrobial resistance is becoming more prevalent. Hinokitiol, which is isolated from trees in the cypress family, has been demonstrated to exert antibacterial activity against S. pneumoniae in vitro regardless of antimicrobial resistance. In this study, the efficacy of hinokitiol was investigated in a mouse pneumonia model. Male 8-week-old BALB/c mice were intratracheally infected with S. pneumoniae strains D39 (antimicrobial susceptible) and NU4471 (macrolide resistant). After 1 h, hinokitiol was injected via the tracheal route. Hinokitiol significantly decreased the number of S. pneumoniae in the bronchoalveolar lavage fluid (BALF) and the concentration of pneumococcal DNA in the serum, regardless of whether bacteria were resistant or susceptible to macrolides. In addition, hinokitiol decreased the infiltration of neutrophils in the lungs, as well as the concentration of inflammatory cytokines in the BALF and serum. Repeated hinokitiol injection at 18 h intervals showed downward trend in the number of S. pneumoniae in the BALF and the concentration of S. pneumoniae DNA in the serum with the number of hinokitiol administrations. These findings suggest that hinokitiol reduced bacterial load and suppressed excessive host immune response in the pneumonia mouse model. Accordingly, hinokitiol warrants further exploration as a potential candidate for the treatment of pneumococcal pneumonia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Infective Agents / pharmacology*
  • Anti-Infective Agents / therapeutic use
  • Bronchoalveolar Lavage Fluid / microbiology
  • Chemokine CXCL1 / blood
  • Chemokine CXCL1 / metabolism
  • Cytokines / blood
  • Cytokines / metabolism
  • Drug Resistance, Bacterial
  • Interleukin-6 / blood
  • Interleukin-6 / metabolism
  • Lung / immunology
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Monoterpenes / pharmacology*
  • Monoterpenes / therapeutic use
  • Neutrophil Infiltration
  • Neutrophils / cytology
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Pneumonia, Pneumococcal / drug therapy
  • Pneumonia, Pneumococcal / microbiology
  • Pneumonia, Pneumococcal / pathology*
  • Streptococcus pneumoniae / isolation & purification*
  • Streptococcus pneumoniae / pathogenicity
  • Tropolone / analogs & derivatives*
  • Tropolone / pharmacology
  • Tropolone / therapeutic use

Substances

  • Anti-Infective Agents
  • Chemokine CXCL1
  • Cytokines
  • Interleukin-6
  • Monoterpenes
  • Tropolone
  • beta-thujaplicin

Grants and funding

This work was supported by the Japan society for the promotion of science (JSPS) KAKENHI Grant (Numbers JP20H03858 to YT; JP20K09903 to HD). A comprehensive list of grants funding is available on the JSPS KAKENHI website (https://kaken.nii.ac.jp/en/). HD received funding from the Kobayashi International Scholarship Foundation (https://www.kisf.or.jp/english/) and the Takeda Science Foundation (https://www.takeda-sci.or.jp/business/abroad_e.html). Kobayashi Pharmaceutical, Co., Ltd provided support in the form of salaries for EK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.