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Design and Synthesis of C7-N-acetylneuraminic Acid Analogues as Potential Bacterial Sialic Acid Transport Inhibitors

Kulesh, Maria LU (2024) KEMR30 20241
Department of Chemistry
Abstract
This project is part of a larger effort to design bacterial sialic acid inhibitors based on sialic acid, Neu5Ac. The emergence of antimicrobial resistance is a major concern for the public health and causes a significant number of deaths globally each year. There is an urgent need to discover novel antibacterials to still be able to cure infections in the future.
This project explores a strategy based on sialic acid - a 9-carbon sugar found on the terminal positions of the carbohydrate chains covering the cell surfaces. Several pathogens may utilize sialic acid for molecular mimicry or as an energy source. The idea is to block the sialic acid transport into the cell, thus preventing the bacteria from colonizing and infecting the host.
... (More)
This project is part of a larger effort to design bacterial sialic acid inhibitors based on sialic acid, Neu5Ac. The emergence of antimicrobial resistance is a major concern for the public health and causes a significant number of deaths globally each year. There is an urgent need to discover novel antibacterials to still be able to cure infections in the future.
This project explores a strategy based on sialic acid - a 9-carbon sugar found on the terminal positions of the carbohydrate chains covering the cell surfaces. Several pathogens may utilize sialic acid for molecular mimicry or as an energy source. The idea is to block the sialic acid transport into the cell, thus preventing the bacteria from colonizing and infecting the host.
Previous work has been focused on modifying the 4-OH, 5-NHAc and 9-OH positions of sialic acid, but little is yet known about the role of the glycerol tail for protein binding. This project aimed to expand the compound library, by replacing the glycerol tail with other moieties, with the goal of improving binding affinity.
To achieve this, the glycerol tail was transformed into an aldehyde and new moieties were successfully installed via different linkers. A new class of compounds – 1,7-bicyclic lactams was accidentally discovered in the process.
The project resulted in a collection of sialic acid analogues based on reductive amination of the C7-aldehyde, but their effect on binding affinity remains to be explored. (Less)
Popular Abstract (Swedish)
I duellen mellan människor och bakterier har båda ett par ess i rockärmen. Människan har utvecklat läkemedel som hämmar bakteriens förmåga till att föröka sig och sprida infektionen vidare. Bakterien i sin tur har utvecklat knep för att komma undan. Under de senare åren hör vi allt oftare om antibiotikaresistens, det vill säga infektioner som inte längre svarar på vanlig behandling och vi behöver därför utveckla nya strategier för att kunna bota dem.
Detta projekt syftar till att framställa ny antibiotika utifrån sialinsyra – ett socker som man kan hitta på cellernas ytor. Sockret utgör en slags QR-kod, som kan användas för att känna av och kommunicera med andra celler i omgivningen. En del bakterier kan förklä sig med sockret, likt ulvar... (More)
I duellen mellan människor och bakterier har båda ett par ess i rockärmen. Människan har utvecklat läkemedel som hämmar bakteriens förmåga till att föröka sig och sprida infektionen vidare. Bakterien i sin tur har utvecklat knep för att komma undan. Under de senare åren hör vi allt oftare om antibiotikaresistens, det vill säga infektioner som inte längre svarar på vanlig behandling och vi behöver därför utveckla nya strategier för att kunna bota dem.
Detta projekt syftar till att framställa ny antibiotika utifrån sialinsyra – ett socker som man kan hitta på cellernas ytor. Sockret utgör en slags QR-kod, som kan användas för att känna av och kommunicera med andra celler i omgivningen. En del bakterier kan förklä sig med sockret, likt ulvar i fårakläder, för att lura kroppens försvar eller använda sockret som energikälla.
Tanken är att förhindra att bakterierna tillgodogör sig sialinsyra genom att sätta en kork på sockertransporten in i bakterien och därmed sätta en käpp i hjulen för en ny infektion. En sådan kork behöver ha rätt form och storlek för att vara effektiv.
I detta arbete framställde vi ett flertal sialinsyreanaloger, det vill säga varianter av sialinsyra. Dessa kommer senare kunna testas för att se ifall de kan blockera sialinsyretransporten in i bakterien. (Less)
Please use this url to cite or link to this publication:
author
Kulesh, Maria LU
supervisor
organization
course
KEMR30 20241
year
type
H2 - Master's Degree (Two Years)
subject
keywords
AMR, bacterial transporter, drug design, organic chemistry, sialic acid
language
English
id
9166672
date added to LUP
2024-06-27 08:35:13
date last changed
2024-06-27 08:35:13
@misc{9166672,
  abstract     = {{This project is part of a larger effort to design bacterial sialic acid inhibitors based on sialic acid, Neu5Ac. The emergence of antimicrobial resistance is a major concern for the public health and causes a significant number of deaths globally each year. There is an urgent need to discover novel antibacterials to still be able to cure infections in the future.
This project explores a strategy based on sialic acid - a 9-carbon sugar found on the terminal positions of the carbohydrate chains covering the cell surfaces. Several pathogens may utilize sialic acid for molecular mimicry or as an energy source. The idea is to block the sialic acid transport into the cell, thus preventing the bacteria from colonizing and infecting the host.
Previous work has been focused on modifying the 4-OH, 5-NHAc and 9-OH positions of sialic acid, but little is yet known about the role of the glycerol tail for protein binding. This project aimed to expand the compound library, by replacing the glycerol tail with other moieties, with the goal of improving binding affinity.
To achieve this, the glycerol tail was transformed into an aldehyde and new moieties were successfully installed via different linkers. A new class of compounds – 1,7-bicyclic lactams was accidentally discovered in the process.
The project resulted in a collection of sialic acid analogues based on reductive amination of the C7-aldehyde, but their effect on binding affinity remains to be explored.}},
  author       = {{Kulesh, Maria}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Design and Synthesis of C7-N-acetylneuraminic Acid Analogues as Potential Bacterial Sialic Acid Transport Inhibitors}},
  year         = {{2024}},
}