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Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA..
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
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2009 (Engelska)Ingår i: Nature Chemical Biology, ISSN 1552-4450, EISSN 1552-4469, Vol. 5, nr 12, s. 913-919Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Curli are functional extracellular amyloid fibers produced by uropathogenic Escherichia coli (UPEC) and other Enterobacteriaceae. Ring-fused 2-pyridones, such as FN075 and BibC6, inhibited curli biogenesis in UPEC and prevented the in vitro polymerization of the major curli subunit protein CsgA. The curlicides FN075 and BibC6 share a common chemical lineage with other ring-fused 2-pyridones termed pilicides. Pilicides inhibit the assembly of type

1pili, which are required for pathogenesis during urinary tract infection. Notably, the curlicides retained pilicide activities and inhibited both curli-dependent and type 1–dependent biofilms. Furthermore, pretreatment of UPEC with FN075 significantly attenuated virulence in a mouse model of urinary tract infection. Curli and type 1pili exhibited exclusive and independent roles in promoting UPEC biofilms, and curli provided a fitness advantage in vivo. Thus, the ability of FN075 to block the biogenesis of both curli and type 1pili endows unique anti-biofilm and anti-virulence activities on these compounds.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group , 2009. Vol. 5, nr 12, s. 913-919
Identifikatorer
URN: urn:nbn:se:umu:diva-26861DOI: 10.1038/nchembio.242OAI: oai:DiVA.org:umu-26861DiVA, id: diva2:274476
Anmärkning
Published online 25 October 2009Tillgänglig från: 2009-10-29 Skapad: 2009-10-29 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Pilicides and Curlicides: Design, synthesis, and evaluation of novel antibacterial agents targeting bacterial virulence
Öppna denna publikation i ny flik eller fönster >>Pilicides and Curlicides: Design, synthesis, and evaluation of novel antibacterial agents targeting bacterial virulence
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

New strategies are needed to counter the growing problem of bacterial resistance to antibiotics. One such strategy is to design compounds that target bacterial virulence, which could work separately or in concert with conventional bacteriostatic or bactericidal antibiotics. Pilicides are a class of compounds based on a ring-fused 2-pyridone scaffold that target bacterial virulence by blocking the chaperone/usher pathway in E. coli and thereby inhibit the assembly of pili. This thesis describes the design, synthesis, and biological evaluation of compounds based on the pilicide scaffold with the goal of improving the pilicides and expanding their utility. Synthetic pathways have been developed to enable the introduction of substituents at the C-2 position of the pilicide scaffold. Biological evaluation of these compounds demonstrated that some C-2 substituents give rise to significant increases in potency. X-ray crystallography was used to elucidate the structural basis of this improved biological activity. Furthermore, improved methods for the preparation of oxygen-analogues and C-7 substituted derivatives of the pilicide scaffold have been developed. These new methods were used in combination with existing strategies to decorate the pilicide scaffold as part of a multivariate design approach to improve the pilicides and generate structure activity relationships (SARs).

Fluorescent pilicides were prepared using a strategy where selected substituents were replaced with fluorophores having similar physicochemical properties as the original substituents. Many of the synthesized fluorescent compounds displayed potent pilicide activities and can thus be used to study the complex interactions between pilicide and bacteria. For example, when E. coli was treated with fluorescent pilicides, it was found that the compounds were not uniformly distributed throughout the bacterial population, suggesting that the compounds are primarily associated to bacteria with specific properties.

Finally, by studying compounds designed to inhibit the aggregation of Aβ, it was found that some compounds based on the pilicide scaffold inhibit the formation of the functional bacterial amyloid fibers known as curli; these compounds are referred to as 'curlicides'. Some of the curlicides also prevent the formation of pili and thus exhibit dual pilicide-curlicide activity. The potential utility of such 'dual-action' compounds was highlighted by a study of one of the more potent dual pilicide-curlicides in a murine UTI model were the compound was found to significantly attenuate virulence in vivo.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, Kemiska Institutionen, 2010. s. 83
Nyckelord
pilicide, curlicide, anti-virulence, chaperone/usher pathway, antibacterial, pili, curli, Escherichia coli, biofilm inhibitor, 2-pyridone, peptidomimetic
Nationell ämneskategori
Organisk kemi Organisk kemi Läkemedelskemi Organisk kemi Infektionsmedicin
Forskningsämne
bioorganisk kemi; infektionssjukdomar; läkemedelskemi; organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-37161 (URN)978-91-7459-095-1 (ISBN)
Disputation
2010-11-19, KBC-huset, KB3B1, Umeå Universitet, kemiska institutionen, SE-90187, Umeå, 10:33 (Engelska)
Opponent
Handledare
Tillgänglig från: 2010-10-29 Skapad: 2010-10-21 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Chorell, ErikÅberg, VeronicaAlmqvist, Fredrik

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