Journal
FRONTIERS IN CHEMISTRY
Volume 6, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fchem.2018.00233
Keywords
antibiotic resistance; sialic acids; SiaT; sodium solute symporter; Staphylococcus aureus
Categories
Funding
- Marsden Fund Council [UOC1506, 15-UOA-105]
- US Army Research Laboratory [W911NF-11-1-0481]
- US Army Research Office [W911NF-11-1-0481]
- Swedish Research Council [2011-5790]
- Swedish Research Council Formas [2010-1759, 221-2013-730]
- Swedish Governmental Agency for Innovation Systems (VINNOVA) [2013-04655, 2017-00180]
- Carl Tryggers Stiftelse for Vetenskaplig Forskning [11:147]
- Centre for Antibiotic Resistance Research (CARe) at University of Gothenburg
- EMBO [584-2014]
- Magnus Bergvalls Stiftelse [2014-00536, 2015-00763, 2016-01606]
- Department of Biotechnology [BT/IN/Sweden/41/SR/2013]
- Rutherford Discovery Fellowship [15-MAU-001]
- Swedish Research Council [2013-04655, 2017-00180] Funding Source: Swedish Research Council
- Vinnova [2017-00180, 2013-04655] Funding Source: Vinnova
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Mammalian cell surfaces are decorated with complex glycoconjugates that terminate with negatively charged sialic acids. Commensal and pathogenic bacteria can use host-derived sialic acids for a competitive advantage, but require a functional sialic acid transporter to import the sugar into the cell. This work investigates the sodium sialic acid symporter (SiaT) from Staphylococcus aureus (SaSiaT). We demonstrate that SaSiaT rescues an Escherichia coli strain lacking its endogenous sialic acid transporter when grown on the sialic acids N-acetylneuraminic acid (Neu5Ac) or N-glycolylneuraminic acid (Neu5Gc). We then develop an expression, purification and detergent solubilization system for SaSiaT and demonstrate that the protein is largely monodisperse in solution with a stable monomeric oligomeric state. Binding studies reveal that SaSiaT has a higher affinity for Neu5Gc over Neu5Ac, which was unexpected and is not seen in another SiaT homolog. We develop a homology model and use comparative sequence analyses to identify substitutions in the substrate-binding site of SaSiaT that may explain the altered specificity. SaSiaT is shown to be electrogenic, and transport is dependent upon more than one Na+ ion for every sialic acid molecule. A functional sialic acid transporter is essential for the uptake and utilization of sialic acid in a range of pathogenic bacteria, and developing new inhibitors that target these transporters is a valid mechanism for inhibiting bacterial growth. By demonstrating a route to functional recombinant SaSiaT, and developing the in vivo and in vitro assay systems, our work underpins the design of inhibitors to this transporter.
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