Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth
Year: 2022
Type: article
Abstract: Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies. The most potent compounds, which have a 180-fold higher affinity compared to the natural substrate, were tested in bacterial growth assays and indicate bacterial growth delay in methicillin-resistant Staphylococcus aureus. This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.
Source: ACS Chemical Biology
Authors: Tiago Bozzola, Mariafrancesca Scalise, Christer U. Larsson, Michael C. Newton-Vesty, Caterina Rovegno, Ankita Mitra, Jonathan Cramer, Weixiao Yuan Wahlgren, Partha Radhakrishnan Santhakumari, Richard E. Johnsson, Oliver Schwardt, Beat Ernst, Rosmarie Friemann, Renwick C. J. Dobson, Cesare Indiveri, Jenny Schelin, Ulf J. Nilsson, Ulf Ellervik
Institutions: University of Basel, Lund University, University of Calabria, University of Canterbury, Heinrich Heine University Düsseldorf, University of Gothenburg, Manipal Academy of Higher Education, Institute for Stem Cell Biology and Regenerative Medicine, Medicon Village, Red Glead Discovery (Sweden), Sahlgrenska University Hospital, The University of Melbourne, Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: Universität Basel, Department of Biotechnology, Ministry of Science and Technology, India, Royal Society Te Apārangi, VINNOVA, Svenska Forskningsrådet Formas, Lunds Universitet, Ministry of Business, Innovation and Employment, Göteborgs Universitet, Ministero dell'Università e della Ricerca, Medical School, University of Michigan, Biomolecular Interaction Centre, University of Canterbury, Marsden Fund, Centre for Antibiotic Resistance Research, University of Gothenburg, H2020 Marie Skłodowska-Curie Actions
Awards: G1016980463, G1076665867, G2757215772, Development of a simple, general and novel assay platform for detecting and quantifying analytes in non-laboratory settings., G5241346672, G5285881022, Sialic Acid Scavenging, Catabolic and Sialylation Pathways: Putative Targets for New Antimicrobial Agents, Multidisciplinary European Joint Doctorate in the Design and Development of Glyco Drugs
OpenAlex ID: W4281667029