Mimicking the human environment in mice reveals that inhibiting biotin biosynthesis is effective against antibiotic-resistant pathogens.
Lindsey A CarfraeCraig R MacNairChristopher M BrownCaressa N TsaiBrent S WeberSoumaya ZlitniVishwas N RaoJoshua ChunMurray S JunopBrian K CoombesEric D BrownPublished in: Nature microbiology (2019)
To revitalize the antibiotic pipeline, it is critical to identify and validate new antimicrobial targets1. In Mycobacteria tuberculosis and Francisella tularensis, biotin biosynthesis is a key fitness determinant during infection2-5, making it a high-priority target. However, biotin biosynthesis has been overlooked for priority pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. This can be attributed to the lack of attenuation observed for biotin biosynthesis genes during transposon mutagenesis studies in mouse infection models6-9. Previous studies did not consider the 40-fold higher concentration of biotin in mouse plasma compared to human plasma. Here, we leveraged the unique affinity of streptavidin to develop a mouse infection model with human levels of biotin. Our model suggests that biotin biosynthesis is essential during infection with A. baumannii, K. pneumoniae and P. aeruginosa. Encouragingly, we establish the capacity of our model to uncover in vivo activity for the biotin biosynthesis inhibitor MAC13772. Our model addresses the disconnect in biotin levels between humans and mice, and explains the failure of potent biotin biosynthesis inhibitors in standard mouse infection models.
Keyphrases
- pseudomonas aeruginosa
- acinetobacter baumannii
- cell wall
- multidrug resistant
- klebsiella pneumoniae
- endothelial cells
- escherichia coli
- drug resistant
- cystic fibrosis
- gram negative
- body composition
- mycobacterium tuberculosis
- physical activity
- gene expression
- genome wide
- biofilm formation
- induced pluripotent stem cells
- human immunodeficiency virus
- hiv infected
- hepatitis c virus