TitleSialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth.
Publication TypeJournal Article
Year of Publication2022
AuthorsBozzola T, Scalise M, Larsson CU, Newton-Vesty MC, Rovegno C, Mitra A, Cramer J, Wahlgren WYuan, Santhakumari PRadhakrish, Johnsson RE, Schwardt O, Ernst B, Friemann R, Dobson RCJ, Indiveri C, Schelin J, Nilsson UJ, Ellervik U
JournalACS Chem Biol
Date Published2022 Jul 15
KeywordsAnti-Bacterial Agents, Kinetics, Methicillin-Resistant Staphylococcus aureus, Microbial Sensitivity Tests, N-Acetylneuraminic Acid

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 . This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.

Alternate JournalACS Chem Biol
PubMed ID35675124
PubMed Central IDPMC9295122