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Sialic Acid 4-N-Piperazine and Piperidine Derivatives Bind with High Affinity to the P. mirabilis Sialic Acid Sodium Solute Symporter

Bozzola, Tiago LU ; Johnsson, Richard E. LU ; Nilsson, Ulf J. LU and Ellervik, Ulf LU orcid (2022) In ChemMedChem 17(23).
Abstract

In search for novel antibacterial compounds, bacterial sialic acid uptake inhibition represents a promising strategy. Sialic acid plays a critical role for growth and colonisation of several pathogenic bacteria, and its uptake inhibition in bacteria was recently demonstrated to be a viable strategy by targeting the SiaT sodium solute symporters from Proteus mirabilis and Staphylococcus aureus. Here we report the design, synthesis and evaluation of potential sialic acid uptake inhibitors bearing 4-N-piperidine and piperazine moieties. The 4-N-derivatives were obtained via 4-N-functionalization with piperidine and piperazine nucleophiles in an efficient direct substitution of the 4-O-acetate of Neu5Ac. Evaluation for binding to bacterial... (More)

In search for novel antibacterial compounds, bacterial sialic acid uptake inhibition represents a promising strategy. Sialic acid plays a critical role for growth and colonisation of several pathogenic bacteria, and its uptake inhibition in bacteria was recently demonstrated to be a viable strategy by targeting the SiaT sodium solute symporters from Proteus mirabilis and Staphylococcus aureus. Here we report the design, synthesis and evaluation of potential sialic acid uptake inhibitors bearing 4-N-piperidine and piperazine moieties. The 4-N-derivatives were obtained via 4-N-functionalization with piperidine and piperazine nucleophiles in an efficient direct substitution of the 4-O-acetate of Neu5Ac. Evaluation for binding to bacterial transport proteins with nanoDSF and ITC revealed compounds possessing nanomolar affinity for the P. mirabilis SiaT symporter. Computational analyses indicate the engagement of a previously untargeted portion of the binding site.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Antibacterial agents, Proteus mirabilis, Sialic acid, Stereoselective amination, Uptake inhibition
in
ChemMedChem
volume
17
issue
23
article number
e202200351
publisher
Wiley-Blackwell
external identifiers
  • pmid:36121381
  • scopus:85139771995
ISSN
1860-7179
DOI
10.1002/cmdc.202200351
project
Design and synthesis of sialic acid derivatives to block bacterial sialic acid uptake
language
English
LU publication?
yes
id
769e3273-0dfe-4e65-9090-78fa822e5611
date added to LUP
2023-01-23 09:19:52
date last changed
2025-03-05 19:51:14
@article{769e3273-0dfe-4e65-9090-78fa822e5611,
  abstract     = {{<p>In search for novel antibacterial compounds, bacterial sialic acid uptake inhibition represents a promising strategy. Sialic acid plays a critical role for growth and colonisation of several pathogenic bacteria, and its uptake inhibition in bacteria was recently demonstrated to be a viable strategy by targeting the SiaT sodium solute symporters from Proteus mirabilis and Staphylococcus aureus. Here we report the design, synthesis and evaluation of potential sialic acid uptake inhibitors bearing 4-N-piperidine and piperazine moieties. The 4-N-derivatives were obtained via 4-N-functionalization with piperidine and piperazine nucleophiles in an efficient direct substitution of the 4-O-acetate of Neu5Ac. Evaluation for binding to bacterial transport proteins with nanoDSF and ITC revealed compounds possessing nanomolar affinity for the P. mirabilis SiaT symporter. Computational analyses indicate the engagement of a previously untargeted portion of the binding site.</p>}},
  author       = {{Bozzola, Tiago and Johnsson, Richard E. and Nilsson, Ulf J. and Ellervik, Ulf}},
  issn         = {{1860-7179}},
  keywords     = {{Antibacterial agents; Proteus mirabilis; Sialic acid; Stereoselective amination; Uptake inhibition}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{23}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{ChemMedChem}},
  title        = {{Sialic Acid 4-N-Piperazine and Piperidine Derivatives Bind with High Affinity to the P. mirabilis Sialic Acid Sodium Solute Symporter}},
  url          = {{http://dx.doi.org/10.1002/cmdc.202200351}},
  doi          = {{10.1002/cmdc.202200351}},
  volume       = {{17}},
  year         = {{2022}},
}