Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth
(2022) In ACS Chemical Biology 17(7). p.1890-1900- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2022-07-15
- type
- Contribution to journal
- publication status
- published
- subject
- in
- ACS Chemical Biology
- volume
- 17
- issue
- 7
- pages
- 11 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:35675124
- scopus:85133525310
- ISSN
- 1554-8929
- DOI
- 10.1021/acschembio.2c00321
- project
- Design and synthesis of sialic acid derivatives to block bacterial sialic acid uptake
- language
- English
- LU publication?
- yes
- id
- 72c62b0b-6414-4628-9f3d-00f627c98b2e
- date added to LUP
- 2022-10-10 09:24:08
- date last changed
- 2024-12-13 08:44:53
@article{72c62b0b-6414-4628-9f3d-00f627c98b2e, abstract = {{<p>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.</p>}}, author = {{Bozzola, Tiago and Scalise, Mariafrancesca and Larsson, Christer U. and Newton-Vesty, Michael C. and Rovegno, Caterina and Mitra, Ankita and Cramer, Jonathan and Wahlgren, Weixiao Yuan and Radhakrishnan Santhakumari, Partha and Johnsson, Richard E. and Schwardt, Oliver and Ernst, Beat and Friemann, Rosmarie and Dobson, Renwick C.J. and Indiveri, Cesare and Schelin, Jenny and Nilsson, Ulf J. and Ellervik, Ulf}}, issn = {{1554-8929}}, language = {{eng}}, month = {{07}}, number = {{7}}, pages = {{1890--1900}}, publisher = {{The American Chemical Society (ACS)}}, series = {{ACS Chemical Biology}}, title = {{Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth}}, url = {{http://dx.doi.org/10.1021/acschembio.2c00321}}, doi = {{10.1021/acschembio.2c00321}}, volume = {{17}}, year = {{2022}}, }