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Title: Development of anti-biofilm agents and elucidation of their mode of action
Authors: Robijns, Stijn
Steenackers, Hans
Hermans, Kim
Dubey, Akanksha
Levin, Jeremy
Ermolatev, Denis
Voet, Arnout
De Maeyer, Marc
Marchal, Kathleen
Marchand, Arnaud
Chaltin, Patrick
Van der Eycken, Erik
De Vos, Dirk
De Keersmaecker, Sigrid
Vanderleyden, Jos
Issue Date: May-2012
Conference: Knowledge for Growth 2012 edition:8 location:ICC, Ghent date:24 May 2012
Article number: Industrial Biotech - 7
Abstract: The objective of our interdisciplinary research consortium is the development of anti-biofilm agents, with a special interest for agents that specifically target biofilms without affecting the bacterial growth. These specific anti-biofilm agents have the advantage of being less prone to the development of resistance than classical biocides or antibiotics. Moreover elucidation of their biofilm-specific mode of action reveals insight into the molecular events of biofilm formation and is likely to result in the identification of new cellular targets for biofilm inhibitors. The anti-biofilm agents have potential to be used in a preventive fashion (e.g. as coatings on medical implants and devices) or to eradicate biofilms (possibly in combination with antibiotics or disinfectants). Salmonella Typhimurium, Pseudomonas aeruginosa and Escherichia coli are the model organisms, against which the anti-biofilm agents are being developed. Our development strategy consists of (i) in vitro and in silico screenings of compound libraries for anti-biofilm agents, (ii) chemical synthesis of a series of analogues of the identified hits, (iii) structure-activity relationship studies (SAR) and structure-toxicity relationship studies, (iv) mode of action studies of the lead compounds combining wet lab (transcriptomics, gene reporter fusion libraries and/or artificial evolution) and bioinformatics approaches and (v) further evaluation and development of the lead compounds (e.g. synergy studies, use of more applied test systems, formulation, effect on multispecies biofilms …).
Results and perspectives
*Brominated furanones have previously been shown to inhibit quorum sensing and biofilm formation of several bacterial species. We synthesized a library of 25 1’-substituted and -unsubstituted 3-alkyl-5-methylene-2(5H)-furanones and 3-alkyl-maleic anhydrides, by using known and newly developed chemistry, and tested their effect against Salmonella biofilms. The most active furanones have IC50 values around 1 µM. The furanones were found to interfere with the synthesis of flagella by Salmonella. Interestingly, pretreatment with furanones rendered Salmonella biofilms more susceptible to antibiotic treatment.
*An in silico screening of the commercial ‘Specs’ small molecule library revealed a 2N-subsituted 2-aminoimidazoline as inhibitor of biofilm formation. Analogues (~250) with either a 2-aminoimidazoline or a 2-aminoimidazole scaffold were synthesized by using newly developed chemistry. (4)5-phenyl-2-amino-1H-imidazole was found to have a moderate inhibitory activity against Salmonella and Pseudomonas biofilm formation. However, substitution of the N1-position, the 2N-position and the 4(5)-phenyl ring enhanced the activity up to 100 times (IC50 ~1 µM). Mode of action studies revealed two possible cellular targets of the imidazoles, which are currently under further investigation. An experimental evolution experiment is being performed to identify additional targets. The 2-aminoimidazoles have been introduced in (i) a battery of anti-biofilm challenge tests (with industrial partners) and (ii) the EU-project COATIM on anti-biofilm coatings for implants.
*A high throughput screening of a library of >20,000 very diverse small-molecules (CD3) resulted in the identification of 140 anti-biofilm agents. Three compound families have been selected for which an early SAR study has been performed and mode of action studies are currently being performed.
Description: Poster
URI: 
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Departement Sociaal-agogisch Werk - IPSOC KATHO
Intellectual Property
Biochemistry, Molecular and Structural Biology Section
Molecular Design and Synthesis
Centre for Surface Chemistry and Catalysis
Centre of Microbial and Plant Genetics

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