Studies on the roles of rffG and rfbB encoding dTDP glucose 4 6 dehydratase in Salmonella Typhimurium

Abstract

Salmonellosis is a major health concern which causes significant morbidity and mortality worldwide. Infection with Salmonella Typhimurium leads to self-limiting diarrhea in healthy individuals and invasive disease in immune-compromised hosts. Emerging drug resistance in Salmonella is making treatment options increasingly challenging. A key barrier for the development of new classes of antibiotics for Gram negative pathogens is presence of the outer membrane. The presence of the outer membrane prevents the entry of many antibiotics rendering them ineffective in their clinical utility. Consequently, research on finding new potential drug targets in Salmonella will have a great impact on food industry and public health worldwide. The bacterial surface is the first point of contact with the host and hence it s a target of a variety of antimicrobial defense mechanisms. Lipopolysaccharide (LPS) and enterobacterial common antigen (ECA) are two important virulence determinants which are present on the outer membrane of S. Typhimurium. LPS consists of three components; Lipid A, core oligosaccharide and O-antigen which comprises structural repeating units of four sugar residues. ECA is made up of repeating trisaccharide units composed of 4-acetamide-4,6-dideoxy-D-galactose, N-acetyl-D-mannosaminuronic acid and N-acetyl-D-glucosamine. The gene cluster rfb encodes genes involved in O-antigen biosynthesis whereas rff codes for genes responsible for ECA biosynthesis. The genes rfbB and rffG encode the protein dTDP-glucose 4,6 -dehydratase, an intermediate in the synthesis of both O-antigen and ECA. Since, the enzyme dTDP-glucose- 4,6-dehydratase is involved in the intermittent steps of the synthesis of both O-antigen and ECA, the functional loss of the enzyme renders the cell incapable of synthesizing both O-antigen and the ECA. The function of dTDP-glucose 4,6-dehydratase in organisms such as Candida and Mycobacterium have been well characterized...