Dataset Information

Efficient construction of diketopiperazine macroarrays through a cyclative-cleavage strategy and their evaluation as luminescence inhibitors in the bacterial symbiont Vibrio fischeri.

ABSTRACT: Diketopiperazines (DKPs) are a well-known class of heterocycles that have emerged as promising biologically active scaffolds. Solid-phase organic synthesis has become an important tool in the combinatorial exploration of these privileged structures, expediting the synthesis and, often, the discovery of active compounds. We recently identified several DKPs that are capable of inhibiting the luminescence response of the bacterial symbiont Vibrio fischeri, and we sought to further test the scope of this biological activity. Herein, we report the synthesis of DKP macroarrays using a SPOT-synthesis approach based on an Ugi/DeBoc/Cyclize strategy. Neither a spacer nor a linker was required for macroarray construction on cellulose support, and the cyclative cleavage produced high purity DKPs in good yields. Using this protocol, we prepared a library of 400 DKPs on cellulose support and evaluated its members as luminescence inhibitors in V. fischeri. We found six DKPs capable of inhibiting luminescence by at least 80% at 500 muM. Collectively, this work serves to further highlight the utility of the small molecule macroarray platform for the synthesis and evaluation of focused libraries.

SUBMITTER: Campbell J

PROVIDER: S-EPMC3175616 | biostudies-literature | 2009 Nov-Dec

REPOSITORIES: biostudies-literature

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Efficient construction of diketopiperazine macroarrays through a cyclative-cleavage strategy and their evaluation as luminescence inhibitors in the bacterial symbiont Vibrio fischeri.

Campbell Jennifer J Blackwell Helen E HE

Journal of combinatorial chemistry 20091101 6

Diketopiperazines (DKPs) are a well-known class of heterocycles that have emerged as promising biologically active scaffolds. Solid-phase organic synthesis has become an important tool in the combinatorial exploration of these privileged structures, expediting the synthesis and, often, the discovery of active compounds. We recently identified several DKPs that are capable of inhibiting the luminescence response of the bacterial symbiont Vibrio fischeri, and we sought to further test the scope of ...[more]

PMID: 19831384

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Project description:Beneficial microbial symbionts are often horizontally acquired by their animal hosts from environmental sources, requiring the symbionts to complete a lifestyle transition from free-living in the environment to association with host tissues. In the model symbiosis between the Hawaiian bobtail squid and its microbial symbiont Vibrio fischeri, one mechanism used to make this transition during host colonization is the formation of biofilm-like aggregates on host mucosa. Extensive work has previously been conducted to isolate the critical factors controlling V. fischeri biofilm formation, yet much remains unknown regarding the full breadth of the biofilm-associated regulon. Here, we probed in vitro models of biofilm formation using transcriptomics, to identify novel regulatory pathways active within biofilms of the V. fischeri type strain ES114. Through comparing the gene-sets which became differentially regulated in multiple biofilm models, we discovered a shared set of 232 genes which demonstrated similar patterns in expression relative to uninduced controls. These genes contained representatives of multiple exopolysaccharide loci, genes involved in flagellar motility, and a diverse collection of other genes. Follow-up analysis suggested that these transcriptomic changes reflected true phenotypic effects, including changes in motility and cyclic-di-GMP production in biofilm-induced backgrounds. Beyond characterizing the shared biofilm response, we additionally profiled the regulatory activity of the sensor kinase RscS. This sensor kinase has previously been characterized to function as a phospho-donor within an established biofilm-inducing phospho-relay, yet our data suggests that RscS moonlights in at least one other phospho-relay that integrates downstream signaling from a homolog of the Vibrio cholerae response regulator VpsR, without a need for its established signaling partners. Overall, this study adds to our understanding of the genes involved in V. fischeri biofilm regulation, while revealing new regulatory pathways branching from previously characterized signaling networks.

Dataset Information

Efficient construction of diketopiperazine macroarrays through a cyclative-cleavage strategy and their evaluation as luminescence inhibitors in the bacterial symbiont Vibrio fischeri.

Publications

Efficient construction of diketopiperazine macroarrays through a cyclative-cleavage strategy and their evaluation as luminescence inhibitors in the bacterial symbiont Vibrio fischeri.

Similar Datasets

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