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Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth

Bozzola, Tiago LU ; Scalise, Mariafrancesca ; Larsson, Christer U. LU ; Newton-Vesty, Michael C. ; Rovegno, Caterina ; Mitra, Ankita LU ; Cramer, Jonathan ; Wahlgren, Weixiao Yuan ; Radhakrishnan Santhakumari, Partha and Johnsson, Richard E. , et al. (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.

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organization
publishing date
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
  • scopus:85133525310
  • pmid:35675124
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
2024-06-13 12:33:02
@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}},
}