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Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. 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, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
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2018 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, nr 9, s. 4165-4175Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein "tunnel" as the main inhibitor binding site (A1), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix−turn−helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-A1 selective PrfA inhibitors with potent antivirulence properties.

Ort, förlag, år, upplaga, sidor
American Chemical Society (ACS), 2018. Vol. 61, nr 9, s. 4165-4175
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
URN: urn:nbn:se:umu:diva-148830DOI: 10.1021/acs.jmedchem.8b00289ISI: 000432204800027PubMedID: 29667825Scopus ID: 2-s2.0-85046422455OAI: oai:DiVA.org:umu-148830DiVA, id: diva2:1217767
Tillgänglig från: 2018-06-13 Skapad: 2018-06-13 Senast uppdaterad: 2018-08-28Bibliografiskt granskad
Ingår i avhandling
1. New alternatives to combat Listeria monocytogenes and Chlamydia trachomatis: Design, synthesis, and evaluation of substituted ring-fused 2-pyridones as anti-virulent agents
Öppna denna publikation i ny flik eller fönster >>New alternatives to combat Listeria monocytogenes and Chlamydia trachomatis: Design, synthesis, and evaluation of substituted ring-fused 2-pyridones as anti-virulent agents
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[sv]
Design, syntes och utvärdering av substituerade ringsammansatta 2-pyridoner med biologisk aktivitet mot Listeria monocytogenes och Chlamydia trachomatis
Abstract [en]

Antibiotic resistance has become a global health burden with the number of resistant bacteria continuously increasing. Antibiotic drugs act by being either bactericidal (killing bacteria) or bacteriostatic (inhibiting growth of bacteria). However, these modes of action increase the selective pressure on the bacteria. An alternative treatment strategy to antibiotics is anti-virulence therapies that inhibits virulence of the pathogenic bacteria. The term “virulence” summarises a number of factors that the bacteria need to colonise a new niche and as a consequence its ability to infect and cause diseases. By inhibiting virulence, instead of killing, the selective pressure on the bacteria can be reduced and consequently decreases the rapid development of resistance. This thesis describes two projects focusing on development of anti-virulence agents, with the ring-fused 2-pyridone scaffold as the central character, targeting the bacteria Listeria monocytogenes and Chlamydia trachomatis.

The first project is targeting L. monocytogenes, which is the cause for listeriosis in humans. This can develop into life-threatening encephalitis and meningitis as well as cause severe complications for developing fetus. The target in L. monocytogenes is the transcriptional regulator PrfA that control almost all virulence factors in this bacterium. We have designed and synthesised potent substituted ring-fused 2-pyridones, which at low micromolar concentrations block activation of the virulence regulator PrfA and thus attenuate the bacterial infection. Co-crystallisation of the active ring-fused 2-pyridones with PrfA resulted in determination of the exact substance interaction site in the protein. This facilitated further structure-based design that resulted in improved compounds capable of attenuating L. monocytogenes in an in vivo model.

The second project targets C. trachomatis, which is the causative agent behind the most common sexually transmitted infection as well as the eye infection trachoma. By structure-activity relationship analysis of previously tested ring-fused 2-pyridones, we have designed and synthesised non-hydrolysable ring-fused 2-pyridone amide isosteres. The most potent analogues inhibit C. trachomatis infectivity at low nanomolar concentrations, without showing host cell toxicity or affecting the viability of commensal microbiota. Introduction of heteroatom substituents at specific sites of the ring-fused 2-pyridone scaffold, resulted in improved pharmacokinetic properties of the analogues and further evaluation in vivo was performed.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2018. s. 86
Nyckelord
Antibiotic resistance, anti-virulence, Listeria monocytogenes, Chlamydia trachomatis, ring-fused 2-pyridone, organic synthesis, structure-based design, PrfA, drug design, structure-activity relationship
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-151128 (URN)978-91-7601-920-7 (ISBN)
Disputation
2018-09-21, KB.E3.03 (Stora hörsalen), KBC-huset, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-08-31 Skapad: 2018-08-28 Senast uppdaterad: 2018-08-29Bibliografiskt granskad

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Kulén, MartinaLindgren, MarieHansen, SabineCairns, Andrew G.Grundström, ChristinBegum, Afshanvan der Lingen, IngeborgBrännström, KristofferHall, MichaelSauer, Uwe H.Johansson, JörgenSauer-Eriksson, A. ElisabethAlmqvist, Fredrik

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Kulén, MartinaLindgren, MarieHansen, SabineCairns, Andrew G.Grundström, ChristinBegum, Afshanvan der Lingen, IngeborgBrännström, KristofferHall, MichaelSauer, Uwe H.Johansson, JörgenSauer-Eriksson, A. ElisabethAlmqvist, Fredrik
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Kemiska institutionenUmeå Centre for Microbial Research (UCMR)Klinisk bakteriologiInstitutionen för molekylärbiologi (Medicinska fakulteten)Molekylär Infektionsmedicin, Sverige (MIMS)Institutionen för medicinsk kemi och biofysik
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