Synthesis of sialic acid 9-C and 3-OH derivatives: the challenge of developing new antibacterial drugs by inhibition of sialic acid uptake
(2018) KEMP31 20171Department of Chemistry
- Abstract
- According to the World Health Organization (WHO), antibiotic resistance is a serious threat to our society. Infections with multi-resistant bacteria are causing increased mortality and social costs. Few new drugs are in the pipeline and no prospective of significantly improving the situation seems to be present.
Sialic acids are a wide family of acidic sugars found in the terminal position of glycan chains. Due to their terminal position and abundance in glycoconjugates, sialic acids are responsible for a wide range of physiological and pathological processes such as cell interaction, communication and information transfer. Bacteria are not able to biosynthesize sialic acid and thus utilize host-derived sialic acid for different... (More) - According to the World Health Organization (WHO), antibiotic resistance is a serious threat to our society. Infections with multi-resistant bacteria are causing increased mortality and social costs. Few new drugs are in the pipeline and no prospective of significantly improving the situation seems to be present.
Sialic acids are a wide family of acidic sugars found in the terminal position of glycan chains. Due to their terminal position and abundance in glycoconjugates, sialic acids are responsible for a wide range of physiological and pathological processes such as cell interaction, communication and information transfer. Bacteria are not able to biosynthesize sialic acid and thus utilize host-derived sialic acid for different purposes. In the first place, bacteria catabolize sialic acid as a convenient source of carbon and nitrogen. Additionally, some pathogenic bacteria have developed mechanisms to glycosylate their lipopolysaccharides (LPS), masking them from the human immune system. This immune-evasion mechanism is called “molecular mimicry”.
A recent collaboration has led to the characterisation of a bacterial sialic acid transporter, a sodium solute symporter (SSS) protein. The aim of the collaboration is the development of sialic acid derivatives with high affinity for the SSS protein and other sialic acid transporters. Inhibiting the sialic acid uptake was proved to block bacterial growth and reduce bacterial resistance to human serum. Sialic acid uptake inhibitors may be a brand-new type of antibiotic agents and thus be new tools in the antibiotic resistance fight.
In this thesis, I focused on the synthesis of 9-C and 3-OH N-acetyl neuraminic acid derivatives, the most abundant sialic acid. The work on position 9 led to the synthesis of five derivatives, characterized by the presence of different functional groups to establish a Structure-Activity Relation (SAR) approach. This work produced the first sialic acid derivative able to bind the SSS protein with higher affinity compared to natural ligands. Furthermore, a synthetic path to develop 3-OH derivatives was tested and found highly reliable, even though no final compound was isolated. (Less) - Popular Abstract
- According to the World Health Organization (WHO), antibiotic resistance is a serious threat to our society. Infections with multi-resistant bacteria are causing increased mortality and social costs. Few new drugs are in the pipeline and no prospective of significantly improving the situation seems to be present.
Sialic acids are a wide family of acidic sugars and are responsible for a wide range of physiological and pathological processes such as cell interaction, communication and information transfer. Bacteria are not able to biosynthesize sialic acid and thus utilize host-derived sialic acid for different purposes. In the first place, bacteria catabolize sialic acid as a convenient source of carbon and nitrogen. Additionally, some... (More) - According to the World Health Organization (WHO), antibiotic resistance is a serious threat to our society. Infections with multi-resistant bacteria are causing increased mortality and social costs. Few new drugs are in the pipeline and no prospective of significantly improving the situation seems to be present.
Sialic acids are a wide family of acidic sugars and are responsible for a wide range of physiological and pathological processes such as cell interaction, communication and information transfer. Bacteria are not able to biosynthesize sialic acid and thus utilize host-derived sialic acid for different purposes. In the first place, bacteria catabolize sialic acid as a convenient source of carbon and nitrogen. Additionally, some pathogenic bacteria have developed the ability to use host sialic acid to avoid the human immune system, in a mechanism called “molecular mimicry”.
In this thesis, I have worked on the synthesis of sialic acid derivatives. The aim is to fight the utilisation of sialic acid by bacteria, thus developing molecules with potential antibacterial properties. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9009011
- author
- Bozzola, Tiago LU
- supervisor
-
- Ulf Nilsson LU
- organization
- course
- KEMP31 20171
- year
- 2018
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Sialic acid, medicinal chemistry, antibiotics, organic chemistry, organisk kemi
- language
- English
- id
- 9009011
- date added to LUP
- 2020-05-19 08:21:59
- date last changed
- 2020-05-19 08:21:59
@misc{9009011,
abstract = {{According to the World Health Organization (WHO), antibiotic resistance is a serious threat to our society. Infections with multi-resistant bacteria are causing increased mortality and social costs. Few new drugs are in the pipeline and no prospective of significantly improving the situation seems to be present.
Sialic acids are a wide family of acidic sugars found in the terminal position of glycan chains. Due to their terminal position and abundance in glycoconjugates, sialic acids are responsible for a wide range of physiological and pathological processes such as cell interaction, communication and information transfer. Bacteria are not able to biosynthesize sialic acid and thus utilize host-derived sialic acid for different purposes. In the first place, bacteria catabolize sialic acid as a convenient source of carbon and nitrogen. Additionally, some pathogenic bacteria have developed mechanisms to glycosylate their lipopolysaccharides (LPS), masking them from the human immune system. This immune-evasion mechanism is called “molecular mimicry”.
A recent collaboration has led to the characterisation of a bacterial sialic acid transporter, a sodium solute symporter (SSS) protein. The aim of the collaboration is the development of sialic acid derivatives with high affinity for the SSS protein and other sialic acid transporters. Inhibiting the sialic acid uptake was proved to block bacterial growth and reduce bacterial resistance to human serum. Sialic acid uptake inhibitors may be a brand-new type of antibiotic agents and thus be new tools in the antibiotic resistance fight.
In this thesis, I focused on the synthesis of 9-C and 3-OH N-acetyl neuraminic acid derivatives, the most abundant sialic acid. The work on position 9 led to the synthesis of five derivatives, characterized by the presence of different functional groups to establish a Structure-Activity Relation (SAR) approach. This work produced the first sialic acid derivative able to bind the SSS protein with higher affinity compared to natural ligands. Furthermore, a synthetic path to develop 3-OH derivatives was tested and found highly reliable, even though no final compound was isolated.}},
author = {{Bozzola, Tiago}},
language = {{eng}},
note = {{Student Paper}},
title = {{Synthesis of sialic acid 9-C and 3-OH derivatives: the challenge of developing new antibacterial drugs by inhibition of sialic acid uptake}},
year = {{2018}},
}