Mimicking the human environment in mice reveals that inhibiting biotin biosynthesis is effective against antibiotic-resistant pathogens

Abstract

To revitalize the antibiotic pipeline, it is critical to identify and validate new antimicrobial targets 1 . In Mycobacteria tuberculosis and Francisella tularensis , biotin biosynthesis is a key fitness determinant during infection 2 – 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 models 6 – 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. A modified mouse model that mimics human serum levels of biotin shows that inhibition of biotin synthesis can effectively treat infections caused by diverse antibiotic-resistant pathogens.