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Discovery of three new binding sites and modes of ring-fused 2-pyridones to PrfA: How can they contribute to drug design?
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.ORCID-id: 0000-0001-7301-8445
Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
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(engelsk)Manuskript (preprint) (Annet vitenskapelig)
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Identifikatorer
URN: urn:nbn:se:umu:diva-188505OAI: oai:DiVA.org:umu-188505DiVA, id: diva2:1602046
Tilgjengelig fra: 2021-10-11 Laget: 2021-10-11 Sist oppdatert: 2021-12-20
Inngår i avhandling
1. Disarming bacteria: a structure-based approach to design an anti-virulence drug against Listeria monocytogenes
Åpne denne publikasjonen i ny fane eller vindu >>Disarming bacteria: a structure-based approach to design an anti-virulence drug against Listeria monocytogenes
2021 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Alternativ tittel[sv]
Avväpning av bakterier : ett strukturellt tillvägagångssätt för utvecklingen av ett anti-virulent läkemedel mot Listeria monocytogenes
Abstract [en]

Antibiotic resistances are one of the biggest threats to global health and if we don’t change our behavior and way of using antibiotics we will end up in a ‘post-antibiotic era’, in which common infections and minor injuries can once kill again and up to 10 million deaths per year may occur by 2050. Therefore, there is a high need for new anti-bacterial drugs, especially of alternatives to existing antibiotics with already described resistances. Classical antibiotics target the essential processes of survival and growth in bacteria and therefore put a high selective pressure on them to develop resistances. In contrast, the ability to infect or damage a host, the virulence, is less essential for bacteria. Thus, targeting the virulence is supposed to cause a lower selective pressure and this alternative mode-of-action could help to decelerate the development of antibiotic resistances.

The aims in this work were to proceed with the structure-based design of an anti-virulence drug against the food-borne pathogen Listeria monocytogenes, but also to deepen our understanding of the complex regulation system for the virulence of this bacterium. PrfA, the master regulator of virulence in Listeria monocytogenes, is a member of a large family of bacterial transcription factors, which are regulated by a conformational change and allosteric modulation by different regulator molecules. Furthermore, its critical role in virulence regulations makes is a suitable target for an anti-virulence drug. In this work new lead compounds based on the previously identified ring-fused 2-pyridone scaffold were designed, synthesized and analyzed by different biological, biophysical, computational and structural biology methods. Three new binding sites and binding modes of these compounds in PrfA were evaluated for their potential use in future designs and a compound with improved activity was identified. In a second study another structurally different lead compound was discovered to inhibit PrfA. Furthermore, the studies on proposed natural regulators of PrfA uncovered the underlying mechanism for the virulence regulation by the peptide signature of the environment and in a follow-up study the structural basis of the binding of inhibitory peptides to PrfA was further investigated. Finally, a structural review on all available structure of PrfA provided more insights into the allosteric regulation mechanism of PrfA activity.

This work will hopefully support in the successful development of an anti-virulence drug against Listeria monocytogenes and thus contribute to the reduction of the problem of antibiotic resistances.

sted, utgiver, år, opplag, sider
Umeå: Umeå University, 2021. s. 91
Emneord
antibiotic resistances, anti-virulence drug, Listeria monocytogenes, virulence regulation, PrfA, structure-based drug design, ring-fused 2-pyridones, allosteric regulation
HSV kategori
Forskningsprogram
biokemi; läkemedelskemi; molekylär cellbiologi; medicinsk biokemi; molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-188507 (URN)978-91-7855-677-9 (ISBN)978-91-7855-676-2 (ISBN)
Disputas
2021-11-04, Glasburen, KBC + Zoom, Linnaeus väg 6, Umeå, 10:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2021-10-14 Laget: 2021-10-11 Sist oppdatert: 2022-01-28bibliografisk kontrollert

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Oelker, MelanieVielfort, KatarinaLindgren, CeciliaLindgren, MarieGrundström, ChristinKulén, Martinavan der Lingen, IngeborgTyagi, MohitBegum, AfshanHall, MichaelLindgren, Anders E.Singh, PardeepJohansson, JörgenAlmqvist, FredrikSauer-Eriksson, A. Elisabeth

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Oelker, MelanieVielfort, KatarinaLindgren, CeciliaLindgren, MarieGrundström, ChristinKulén, Martinavan der Lingen, IngeborgTyagi, MohitBegum, AfshanHall, MichaelLindgren, Anders E.Singh, PardeepJohansson, JörgenAlmqvist, FredrikSauer-Eriksson, A. Elisabeth
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