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Pilicides and Curlicides: Design, synthesis, and evaluation of novel antibacterial agents targeting bacterial virulence
Umeå University, Faculty of Science and Technology, Department of Chemistry. (Fredrik Almqvist)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, Kemiska Institutionen , 2010. , 83 p.
Keyword [en]
pilicide, curlicide, anti-virulence, chaperone/usher pathway, antibacterial, pili, curli, Escherichia coli, biofilm inhibitor, 2-pyridone, peptidomimetic
National Category
Organic Chemistry Organic Chemistry Medicinal Chemistry Organic Chemistry Infectious Medicine
Research subject
Biorganic Chemistry; Infectious Diseases; läkemedelskemi; Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-37161ISBN: 978-91-7459-095-1 (print)OAI: oai:DiVA.org:umu-37161DiVA: diva2:358229
Public defence
2010-11-19, KBC-huset, KB3B1, Umeå Universitet, kemiska institutionen, SE-90187, Umeå, 10:33 (English)
Opponent
Supervisors
Available from: 2010-10-29 Created: 2010-10-21 Last updated: 2011-05-16Bibliographically approved
List of papers
1. Diverse functionalization of Thiazolo ring-fused 2-Pyridones
Open this publication in new window or tab >>Diverse functionalization of Thiazolo ring-fused 2-Pyridones
2007 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 13, 4917-4924 p.Article in journal (Refereed) Published
Abstract [en]

Thiazolo ring-fused 2-pyridones have proven to be highly interesting scaffolds for the development of biologically active compounds. Many methods are today available to introduce a variety of substituents in the 2-pyridone part of the heterocycle. Herein we disclose how a diverse set of substituents can be introduced in the thiazolo ring, with possibilities to vary also the spatial arrangement of the substituents. A key intermediate is the oxidized framework 9 for which an effective synthesis is described. The thiazolo part of this system can be substituted either via conjugate additions, resulting in trans selectivity, or via microwave-assisted Heck couplings that result in unsaturated aryl-substituted analogues. The scaffold can also be lithiated followed by the addition of various electrophiles, which increases the diversification potential substantially, as exemplified with the introduction of halogens, alkyl, acyl, and amide substituents.

Place, publisher, year, edition, pages
Washington, DC 20036, USA: American Chemical Society, 2007
Identifiers
urn:nbn:se:umu:diva-14476 (URN)10.1021/jo0704053 (DOI)
Note
ASAP Web Release Date: 01-Jun-2007Available from: 2007-06-05 Created: 2007-06-05 Last updated: 2017-12-14Bibliographically approved
2. Design and synthesis of C-2 substituted Thiazolo and Dihydrothiazolo ring-fused 2-Pyridones: pilicides with increased antivirulence activity
Open this publication in new window or tab >>Design and synthesis of C-2 substituted Thiazolo and Dihydrothiazolo ring-fused 2-Pyridones: pilicides with increased antivirulence activity
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2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 15, 5690-5695 p.Article in journal (Refereed) Published
Abstract [en]

Pilicides block pili formation by binding to pilus chaperones and blocking their function in the chaperone/usher pathway in E. coli. Various C-2 substituents were introduced on the pilicide scaffold by design and synthetic method developments. Experimental evaluation showed that proper substitution of this position affected the biological activity of the compound. Aryl substituents resulted in pilicides with significantly increased potencies as measured in pili-dependent biofilm and hemagglutination assays. The structural basis of the PapD chaperone-pilicide interactions was determined by X-ray crystallography.

Place, publisher, year, edition, pages
Washington, USA: American Chemical Society, 2010
Identifiers
urn:nbn:se:umu:diva-35274 (URN)10.1021/jm100470t (DOI)000280523300028 ()20586493 (PubMedID)
Available from: 2010-08-11 Created: 2010-08-11 Last updated: 2017-12-12Bibliographically approved
3. Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity
Open this publication in new window or tab >>Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity
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2011 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 46, no 4, 1103-1116 p.Article in journal (Refereed) Published
Abstract [en]

Pilicides are a class of compounds that attenuate virulence in Gram negative bacteria by blocking the chaperone/usher pathway in Escherichia coli. It has also been shown that compounds derived from the peptidomimetic scaffold that the pilicides are based on can prevent both Aβ aggregation and curli formation. To facilitate optimizations towards the different targets, a new synthetic platform has been developed that enables fast and simple introduction of various substituents in position C-7 on the peptidomimetic scaffold. Importantly, this strategy also enables introduction of previously unattainable heteroatoms in this position. Pivotal to the synthetic strategy is the synthesis of a C-7 bromomethyl substituted derivative of the ring-fused dihydrothiazolo 2-pyridone pilicide scaffold. From this versatile and reactive intermediate various heteroatom-linked substituents could be introduced on the scaffold including amines, ethers, amides and sulfonamides. In addition, carbon-carbon bonds could be introduced to the sp(3)-hybridized bromomethyl substituted scaffold by Suzuki-Miyaura cross couplings. Evaluation of the 24 C-7 substituted compounds in whole-bacterial assays provided important structure-activity data and resulted in the identification of a number of new pilicides with activity as good or better than those developed previously.

Place, publisher, year, edition, pages
Elsevier Masson SAS, 2011
Keyword
Pilicide, Anti-virulence, 2-Pyridone, peptidomimetic
National Category
Infectious Medicine Organic Chemistry Inorganic Chemistry Medicinal Chemistry Organic Chemistry
Research subject
Biorganic Chemistry; Infectious Diseases; läkemedelskemi; Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-43916 (URN)10.1016/j.ejmech.2011.01.025 (DOI)21316127 (PubMedID)
Available from: 2011-05-16 Created: 2011-05-16 Last updated: 2017-12-11Bibliographically approved
4. Improved procedure for the enantioselective synthesis of dihydrooxazolo and dihydrothiazolo ring-fused 2-pyridones
Open this publication in new window or tab >>Improved procedure for the enantioselective synthesis of dihydrooxazolo and dihydrothiazolo ring-fused 2-pyridones
2010 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, no 18, 2461-2463 p.Article in journal (Refereed) Published
Abstract [en]

Improved procedures to synthesize enantioselectively analogues of a peptidomimetic scaffold with high biological relevance have been developed. Experimental design led to a general method for the preparation of dihydrooxazolo ring-fused 2-pyridones in good yields and high enantiomeric purity. The knowledge gained from this was also used to improve the microwave-accelerated synthesis of dihydrothiazolo ring-fused 2-pyridones to give complete stereo retention and high yields.

Place, publisher, year, edition, pages
Elsevier Ltd, 2010
Keyword
2-Pyridone, PPTS, Peptidomimetic, Enantioselective, Pilicide, Curlicide
Identifiers
urn:nbn:se:umu:diva-32675 (URN)10.1016/j.tetlet.2010.02.162 (DOI)000276972200020 ()
Available from: 2010-03-22 Created: 2010-03-22 Last updated: 2017-12-12Bibliographically approved
5. Design and synthesis of fluorescently labeled pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms
Open this publication in new window or tab >>Design and synthesis of fluorescently labeled pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Pilicides and curlicides block formation of the E. coli virulence factors pili and curli. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved using a strategy where key pilicide and curlicide substituents were replaced by fluorophores having similar physicochemical properties. The resulting fluorescent compounds had improved anti-virulence activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing both coumarin and 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide scaffold. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated to the bacteria and seem to discriminate between different bacteria in a population.

National Category
Infectious Medicine Organic Chemistry Organic Chemistry Medicinal Chemistry Organic Chemistry
Research subject
Biorganic Chemistry; Infectious Diseases; läkemedelskemi; Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-37170 (URN)
Available from: 2010-10-21 Created: 2010-10-21 Last updated: 2011-02-18Bibliographically approved
6. Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation
Open this publication in new window or tab >>Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation
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2009 (English)In: Nature Chemical Biology, ISSN 1552-4450, EISSN 1552-4469, Vol. 5, no 12, 913-919 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2009
Identifiers
urn:nbn:se:umu:diva-26861 (URN)10.1038/nchembio.242 (DOI)
Note
Published online 25 October 2009Available from: 2009-10-29 Created: 2009-10-29 Last updated: 2012-08-10Bibliographically approved

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