Journal article
Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth
T Bozzola, M Scalise, CU Larsson, MC Newton-Vesty, C Rovegno, A Mitra, J Cramer, WY Wahlgren, P Radhakrishnan Santhakumari, RE Johnsson, O Schwardt, B Ernst, R Friemann, RCJ Dobson, C Indiveri, J Schelin, UJ Nilsson, U Ellervik
ACS Chemical Biology | Published : 2022
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 a..
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Awarded by Centre for Antibiotic Resistance Research, University of Gothenburg
Funding Acknowledgements
This work was supported by the European Joint Doctorate educational training network in Glyco-Drug Discovery and Development (PhD4GlycoDrug, Marie Sklodovska-Curie grant agreement no. 765581), the project "SI. F. I.PA.CRO.DE..Sviluppo e industrializzazione farmaci innovativi per terapia molecolare personalizzata PA.CRO.DE." PON ARS01_00568, the Swedish Research Council Formas 2212013-730, the Swedish Governmental Agency for Innovation Systems Indo-Swedish Innovation call: Health and Disease Prevention, grant#2017-00180, DBT-Indo Swedish grant (BT/IN/SWEDEN/41/SR/2013), the New Zealand Royal Society Marsden Fund (contracts UOC1506 and UOC1910), the Ministry of Business, Innovation and Employment Smart Ideas grant (contract UOCX1706), and the Biomolecular Interaction Centre, the Centre for Antibiotic Resistance Research (CARe) at the University of Gothenburg and Lund University.