Design and Synthesis of Sialic Acid Derivatives - the Potential of 7-ethers as Bacterial Inhibitors
(2025) KASM05 20251Centre for Analysis and Synthesis
- Abstract
- With antimicrobial resistance emerging, this project is part of a larger effort to design novel antibacterial substances combating bacterial infections. On the road towards this, sialic acids have become of large interest. Having a vital role within cell signalling, adhesion and recognition in the human body, these 9-carbon α-keto sugars have opened a door for bacterial survival. By the help of sialic acid transporting proteins, bacteria have found a way to utilize host-derived sialic acids for energy and molecular mimicry. The hypothesis is that these mechanisms can be hindered by sialic acid analogues of enhanced affinity for the transport proteins. By the binding of such synthetic molecules to the protein, sialic acid uptake could be... (More)
- With antimicrobial resistance emerging, this project is part of a larger effort to design novel antibacterial substances combating bacterial infections. On the road towards this, sialic acids have become of large interest. Having a vital role within cell signalling, adhesion and recognition in the human body, these 9-carbon α-keto sugars have opened a door for bacterial survival. By the help of sialic acid transporting proteins, bacteria have found a way to utilize host-derived sialic acids for energy and molecular mimicry. The hypothesis is that these mechanisms can be hindered by sialic acid analogues of enhanced affinity for the transport proteins. By the binding of such synthetic molecules to the protein, sialic acid uptake could be blocked, possibly limiting nutrient availability and obstructing molecular mimicry – leaving less room for the bacteria to survive.
Previous work has focused on modifications of the most abundant sialic acid variant, Neu5Ac, where halogenated aromatic substitutions on the fourth and seventh positions were found promising. The latter also gaining knowledge about the importance of the glycerol tail of Neu5Ac. Expanding the work of C7-analogues, this project aimed at creating 7-ethers corresponding to the previously found promising C7-Nitrogen-analogues, with the goal of improving binding affinity and expand the knowledge about the SAR of Neu5Ac.
To achieve this, the glycerol tail was successfully cleaved to a simple alcohol, and a tosylate was installed. Substitution with phenols without protection of the acetamide was found unsuccessful, and instead a bicyclic sugar comprising an oxazine-moiety was formed. The binding affinity of the simple alcohol and oxazine-derivative may be tested, to increase the understanding of how substrates bind to bacterial target proteins. The potential of 7-ethers as bacterial inhibitors remains to be explored. (Less) - Popular Abstract (Swedish)
- Sedan upptäckten av penicillin har mänskligheten lyckats kringgå bakteriella infektioner som tidigare varit dödliga. Men i takt med att användningen av antibiotika ökat, har bakterierna lärt sig att kringgå det. Dessa så kallade resistenta bakterier utgör ett stort hot mot människan, eftersom de i nuläget är svåra att stoppa – med följden att vissa bakteriella infektioner kanske återigen kommer klassas som dödliga.
I jakten på nya läkemedel för att bekämpa bakterier är en speciell typ av socker av intresse. Denna kolhydrat, kallad sialinsyra, finns på våra cellers ytor, där de fungerar som ett slags ID-kort. De celler som kan visa upp sitt sialinsyra-ID kommer tillåtas finnas kvar, medan de andra blir vräkta. Till mänsklighetens stora... (More) - Sedan upptäckten av penicillin har mänskligheten lyckats kringgå bakteriella infektioner som tidigare varit dödliga. Men i takt med att användningen av antibiotika ökat, har bakterierna lärt sig att kringgå det. Dessa så kallade resistenta bakterier utgör ett stort hot mot människan, eftersom de i nuläget är svåra att stoppa – med följden att vissa bakteriella infektioner kanske återigen kommer klassas som dödliga.
I jakten på nya läkemedel för att bekämpa bakterier är en speciell typ av socker av intresse. Denna kolhydrat, kallad sialinsyra, finns på våra cellers ytor, där de fungerar som ett slags ID-kort. De celler som kan visa upp sitt sialinsyra-ID kommer tillåtas finnas kvar, medan de andra blir vräkta. Till mänsklighetens stora förtret är även detta något vissa bakterier verkar ha lärt sig. Genom att knycka ett ID från en mänsklig grann-cell kan bakterien lura kroppen att tro att den är mänsklig, och den får således leva kvar i kroppen och orsaka fullskalig infektion. För detta krävs det dock att bakterien kan ta upp sialinsyran. Vidare betyder detta att om vi med sialinsyra-liknande molekyler kan blockera upptagningsmekanismen, kommer bakterien inte att överleva. En sådan molekyl måste ha både rätt form och storlek för att vara effektiv och det är det syftet med det här arbetet har varit – att finna en passande molekyl.
I detta arbete har viktiga upptäckter gällande sialinsyra-baserad organisk syntes gjorts. Dessutom har en ny typ av molekyl syntetiserats, som i sig fört med sig viktiga lärdomar. Framtida tester av denna molekyl kan medföra ny kunskap om samspelet mellan sialinsyra och passagen in i bakterien, vilket för oss närmare målet att blockera upptagningsmekanismen och därmed finna nya verktyg mot bakteriella infektioner. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9196609
- author
- Karlén, Emma LU
- supervisor
-
- Ulf Nilsson LU
- organization
- course
- KASM05 20251
- year
- 2025
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- AMR, bacterial transporters, drug design, sialic acid, SAR, organic chemistry
- language
- English
- id
- 9196609
- date added to LUP
- 2025-06-18 10:20:47
- date last changed
- 2025-06-18 10:20:47
@misc{9196609,
abstract = {{With antimicrobial resistance emerging, this project is part of a larger effort to design novel antibacterial substances combating bacterial infections. On the road towards this, sialic acids have become of large interest. Having a vital role within cell signalling, adhesion and recognition in the human body, these 9-carbon α-keto sugars have opened a door for bacterial survival. By the help of sialic acid transporting proteins, bacteria have found a way to utilize host-derived sialic acids for energy and molecular mimicry. The hypothesis is that these mechanisms can be hindered by sialic acid analogues of enhanced affinity for the transport proteins. By the binding of such synthetic molecules to the protein, sialic acid uptake could be blocked, possibly limiting nutrient availability and obstructing molecular mimicry – leaving less room for the bacteria to survive.
Previous work has focused on modifications of the most abundant sialic acid variant, Neu5Ac, where halogenated aromatic substitutions on the fourth and seventh positions were found promising. The latter also gaining knowledge about the importance of the glycerol tail of Neu5Ac. Expanding the work of C7-analogues, this project aimed at creating 7-ethers corresponding to the previously found promising C7-Nitrogen-analogues, with the goal of improving binding affinity and expand the knowledge about the SAR of Neu5Ac.
To achieve this, the glycerol tail was successfully cleaved to a simple alcohol, and a tosylate was installed. Substitution with phenols without protection of the acetamide was found unsuccessful, and instead a bicyclic sugar comprising an oxazine-moiety was formed. The binding affinity of the simple alcohol and oxazine-derivative may be tested, to increase the understanding of how substrates bind to bacterial target proteins. The potential of 7-ethers as bacterial inhibitors remains to be explored.}},
author = {{Karlén, Emma}},
language = {{eng}},
note = {{Student Paper}},
title = {{Design and Synthesis of Sialic Acid Derivatives - the Potential of 7-ethers as Bacterial Inhibitors}},
year = {{2025}},
}