ANTIBACTERIAL DRUG DESIGN AND DISCOVERY VIA VITAMIN B1 BIOSYNTHETIC PATHWAY

Abstract

Antibiotics play a vital role in fighting infectious disease caused by bacterial species. Antimicrobial resistance has been shown for every current antibiotic and poses a major health risk. To combat these growing threats to human health; new molecules must be investigated to treat bacterial infection. Chemical inhibition of the vitamin B1 biosynthetic pathway in the bacterial cell was hypothesized to inhibit the survival of bacteria. A series of synthetic molecules, which resemble metabolites of the vitamin B1 pathway, exhibit the inhibition of specific enzymes within this pathway and display initial activity against bacterial growth and survival. The beneficial activity of these new molecules was interpreted both experimentally and computationally. By investigating the relationship between molecular structure and biological function, a second generation of molecules was designed and a number of them were synthesized to be more potent inhibitors of bacterial growth. This iterative process - involving structural design, chemical synthesis and biological evaluation - reveals the vitamin B1 biosynthetic pathway to be a potential new avenue for antibiotic development to treat human infection.