Structural studies of bacterial sialic acid transporters- putative targets for new antimicrobial agents
Rosmarie Friemann. From: University of Gothenburg, to: Stanford School of Medicine, USA.
Our plan is to explore the latest techniques in structure biology using both X-ray free electron laser- and microelectron diffraction to determine structures of bacterial sialic acid transporters.
The structures will have major scientific impact and will hasten the process of understanding how bacteria transport this important sugar molecule over the membrane. The structures will be used for in silico studies to design small lead-like compounds for inhibition studies that will break new ground to develop a new class of anti-microbial agents against this class of pathogens.
Summary of Project Results
Many pathogenic and opportunistic bacteria have evolved the ability to scavenge and metabolise sialic acids - a large family of nine-carbon acidic monosaccharides prevalent in mucus rieh environments. In mammals, sialic acids are primarily found at the terminal end of cell surface glycoconjugates, where they mediate a diverse array of biological functions. As such, bacteria that colonise sialylated environments deploy specific transporters to mediate import of scavenged sialic acid. Once imported to the cytoplasm, bacteria utilise host-derived sialic acids eitherfor molecular mimicry, where sialic acid is incorporated into their surface glycoconjugates, or use sialic acids as sources of carbon, nitrogen and energy.Inhibition of sialic acid transporters has led to bacterial non-virulence in animal models.
However, to date there are no structural data to explain how sialic acid transporters mediate transport across the plasma membrane or how specificity is achieved. Understanding this will be critical for the design of future antimicrobial agents. We have recently determined the first structure of a sialic acid transporter (SiaT) to 1.95 Ä resolution. This is a good stepping-stone for both elucidating the transport mechanism and initiating the first cycles of structure-based drug design.