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Bacterial quorum sensing chemistry : From acyl homoserine lactone analogs in Vibrio fischeri to carbohydrate phosphodiesters in Agrobacterium

Qiang Zhang 1, 2
2 COB - Chimie Organique et Bioorganique
ICBMS - Institut de Chimie et Biochimie Moléculaires et Supramoléculaires
Abstract : The process used by bacteria to coordinate their behavior as a function of their population density, by communicating through small chemical signals (synthesis and sensing), is known as bacterial quorum sensing. This pathway exists in many bacteria, including pathogenic ones. Quorum sensing regulates various gene expressions, including growth, virulence and toxin production. Therefore, the inhibition of quorum sensing is regarded as a promising strategy for preventing bacterial infection. Considering the necessity to diversify antibacterial strategies for facing the issue of antibiotic resistance of bacteria, targeting the QS can propose a complementary approach to existing biological pathways. Focusing on the chemistry of bacterial quorum sensing, this thesis has investigated two different aspects. On one hand, looking for novel QS signals mimics, we discovered new analogs of acyl homoserine lactones (AHLs), able to modulate quorum sensing in Gram-negative bacteria such as Vibrio fischeri. On the other hand, studying carbohydrate phosphodiesters involved in the pathogenicity of Agrobacterium fabrum C58, we developed an efficient method to synthesize a natural agrocinopine as well as some analogs. In the first part, we designed and synthesized novel AHLs analogues including hydrazide, carbamate or thiocarbamate functions, as well as 2-OH AHLs and other analogues based on heterocyclic scaffolds such as imidazole and triazole. We found that AHLs analogues with a carbamate or a thiocarbamate function displayed antagonistic activity whereas the hydrazide anologues were inactive. In the series having a 2-OH function, 2-hydroxy hexanoyl HSL or 2-hydroxy octanoyl HSL were found very active, with opposite activity for each of the two diastereoisomers. In the third set of heterocyclic AHL analogs, it was found that some triazole and imidazole derivatives act as QS antagonists. In the second part, we developed a flexible synthetic route to access the rare glucose-2-phosphate structures, including the native agrocinopine D. Agrocinopines are capable of activating the pathway of quorum sensing in Agrobacterium which in turn activate the virulence factor. In this study, we used an efficient one-pot method to synthesize the precursor of agrocinopine D. It relies on the coupling reaction of the phosphoramidite with benzyl 3,4,6-tri-O-benzyl-β-D-glucopyranoside which is prepared from the commercially available tri-O-benzyl-D-glucal. Biological investigations on the binding mode of this synthetic agrocinopine D with some Agrobacterium proteins are in progress.
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Submitted on : Thursday, May 6, 2021 - 11:27:13 AM
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  • HAL Id : tel-03219205, version 1

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Qiang Zhang. Bacterial quorum sensing chemistry : From acyl homoserine lactone analogs in Vibrio fischeri to carbohydrate phosphodiesters in Agrobacterium. Agricultural sciences. Université de Lyon, 2021. English. ⟨NNT : 2021LYSEI015⟩. ⟨tel-03219205⟩

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