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


Autoři: Chenguang Zhou aff001;  Hao Cai aff001;  Amos Baruch aff001;  Nicholas Lewin-Koh aff002;  Meng Yang aff003;  Fengxun Guo aff003;  Deming Xu aff003;  Rong Deng aff001;  Wouter Hazenbos aff001;  Amrita V. Kamath aff001
Působiště autorů: Research and Early Development, Genentech Inc., South San Francisco, California, United States of America aff001;  Product Development, Genentech Inc., South San Francisco, California, United States of America aff002;  WuXi AppTec (Shanghai) Co., Ltd., Shanghai, China aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224096

Souhrn

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.

Klíčová slova:

Antibacterials – Antibiotics – Bacterial growth – Bioluminescence – Mouse models – Staphylococcus aureus – Vancomycin – Bioluminescence imaging


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2019 Číslo 10