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Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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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. Vol. 46, no 4, 1103-1116 p.
Keyword [en]
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: urn:nbn:se:umu:diva-43916DOI: 10.1016/j.ejmech.2011.01.025PubMedID: 21316127OAI: oai:DiVA.org:umu-43916DiVA: diva2:417290
Available from: 2011-05-16 Created: 2011-05-16 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Pilicides and Curlicides: Design, synthesis, and evaluation of novel antibacterial agents targeting bacterial virulence
Open this publication in new window or tab >>Pilicides and Curlicides: Design, synthesis, and evaluation of novel antibacterial agents targeting bacterial virulence
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
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:nbn:se:umu:diva-37161 (URN)978-91-7459-095-1 (ISBN)
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
2. Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology
Open this publication in new window or tab >>Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotics have been extensively used to treat bacterial infections since Alexander Fleming’s discovery of penicillin 1928. Disease causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. According to the world health organization (WHO) there are about 440 000 new cases of multidrug-resistant tuberculosis emerging annually, causing at least 150 000 deaths. Consequently there is an immense need to develop new types of compounds with new modes of action for the treatment of bacterial infections.

Presented herein is a class of antibacterial ring-fused 2-pyridones, which exhibit inhibitory effects against both the pili assembly system in uropathogenic Escherichia coli (UPEC), named the chaperone usher pathway, as well as polymerization of the major curli subunit protein CsgA, into a functional amyloid fibre. A pilus is an organelle that is vital for the bacteria to adhere to and infect host cells, as well as establish biofilms. Inhibition of the chaperone usher pathway disables the pili assembly machinery, and consequently renders the bacteria avirulent.

The focus of this work has been to develop synthetic strategies to more efficiently alter the substitution pattern of the aforementioned ring-fused 2-pyridones. In addition, asymmetric routes to enantiomerically enriched key compounds and routes to compounds containing BODIPY and coumarin fluorophores as tools to study bacterial virulence mechanisms have been developed. Several of the new compounds have successfully been evaluated as antibacterial agents. In parallel with this research, manipulations of the core structure to create new heterocycle based central fragments for applications in medicinal chemistry have also been performed.   

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2013. 85 p.
Keyword
Synthesis, 2-pyridone, 2-thiazoline, cross coupling, pili, curli, antibacterial
National Category
Natural Sciences
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-68709 (URN)978-91-7459-552-9 (ISBN)
Public defence
2013-05-24, KBC-Huset, KB3B1, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2013-05-03 Created: 2013-04-23 Last updated: 2013-05-03Bibliographically approved

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