Sustained activity of novel THIOMAB antibody-antibiotic conjugate against Staphylococcus aureus in a mouse model: Longitudinal pharmacodynamic assessment by bioluminescence imaging

PLoS One. 2019 Oct 29;14(10):e0224096. doi: 10.1371/journal.pone.0224096. eCollection 2019.

Abstract

Staphylococcus aureus (S. aureus) infections are a leading cause of death by an infectious agent. Survival within host phagocytic cells is one mechanism by which S. aureus evades antibiotic treatment. A novel THIOMAB™ antibody-antibiotic conjugate (TAC) strategy was developed to kill S. aureus intracellularly and mitigate the spread of infection. In this report, we used a longitudinal whole-body bioluminescence imaging method to study the antibacterial dynamics of TAC alone or in combination with vancomycin in a mouse infection model. Injections of stably luminescent S. aureus bacteria into mice resulted in exponential increases in whole body bioluminescence with a reduction in body weight and survival rate. Vancomycin, a standard-of-care antibiotic, suppressed bacterial growth in mice. However, bacterial growth rebounded in these animals once treatment was discontinued. In contrast, single dose of TAC showed rapid reduction of bioluminescence intensity, which persisted for up to 19 days. The combination of TAC and vancomycin achieved a more sustained and significantly greater reduction of bioluminescence compared with vancomycin alone. In summary, the present study showed an imaging method to longitudinally assess antibacterial drug dynamics in mice and demonstrated that TAC monotherapy or in combination with vancomycin had superior and sustained activity compared to vancomycin alone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Antibodies, Bacterial / chemistry
  • Antibodies, Bacterial / pharmacology*
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / pharmacology*
  • Disease Models, Animal*
  • Female
  • Immunoconjugates / pharmacology*
  • Mice
  • Mice, SCID
  • Microbial Sensitivity Tests
  • Staphylococcal Infections / drug therapy*
  • Staphylococcal Infections / microbiology
  • Staphylococcus aureus / drug effects*
  • Vancomycin / pharmacology

Substances

  • Anti-Bacterial Agents
  • Antibodies, Bacterial
  • Antibodies, Monoclonal
  • Immunoconjugates
  • Vancomycin

Grants and funding

The only funding source is Genentech Inc. The funder supported all the experiments and material presented in this manuscript, and financially sponsored Wuxi AppTec, a contract research organization, to perform animal studies. CZ, HC, RD, WH, NLK and AK are current or former employees of Genentech Inc. at the time of these studies. The funding organization did not play any additional roles in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Wuxi AppTec (Shanghai) Co., Ltd, is not a funder. It is a contract research organization sponsored by Genentech Inc. to perform the in vivo experiments. MY, FG, and DX are employees of Wuxi AppTec. The specific roles of all these authors (from Genentech, Inc. or Wuxi AppTec) are articulated in the “author contributions" section.