Matthew Bockman, Neeraj Mishra and Courtney Aldrich* Pages 1 - 38 ( 38 )
Mycobacterium tuberculosis, responsible tuberculosis (TB), remains the leading cause of mortality among infectious diseases worldwide from a single infectious agent, with an estimated 1.7 million deaths in 2016. Biotin is an essential cofactor in M. tuberculosis that is required for lipid biosynthesis and gluconeogenesis. M. tuberculosis relies on de novo biotin biosynthesis to obtain this vital cofactor since it cannot scavenge sufficient biotin from a mammalian host. The biotin biosynthetic pathway in M. tuberculosis has been well studied and rigorously genetically validated providing a solid foundation for medicinal chemistry efforts. This review examines the mechanism and structure of the enzymes involved in biotin biosynthesis and ligation, summarizes the reported genetic validation studies of the pathway, and then analyzes the most promising inhibitors and natural products obtained from structure-based drug design and phenotypic screening.
Tuberculosis, infectious disease, Mycobacterium tuberculosis, biotin, biosynthesis, enzymology, antibiotics
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455