To combat the increased prevalence of antibiotic resistant bacteria, anti-virulence techniques can be utilized as alternative strategies for treating bacterial infections. These strategies target disease-causing virulence factors, impairing bacteria rather than killing them. An example of a virulence factor is the production of biofilms. To form biofilms, bacteria utilize quorum sensing (QS), a form of cell-to-cell communication that utilizes signaling molecules known as autoinducers. Upon reaching a threshold of these molecules, a signaling pathway is initiated, leading to differential gene expression and the formation of biofilms. One class of autoinducers is autoinducer-2 (AI-2), an interspecies signal that is produced from the enzymatic cleavage of S-ribosyl-L-homocysteine (SRH) by the metalloenzyme LuxS. This work aims to inhibit LuxS activity by synthesizing a variety of SRH  analogs utilizing electrophilic groups that will form a covalent bond with the Cys84 residue in the LuxS binding pocket. Here, we have synthesized SRH, which is to be utilized for enzyme-activity assays. A phosphine-mediated Mitsunobu-type reaction was used to couple a ribofuranoside alcohol to a protected L-homocysteine to yield the penultimate precursor to SRH. This precursor was then extensively deprotected, yielding an SRH-trifluoroacetic acid (TFA) salt. To profile the LuxS binding pocket, a series of alkyne probes were synthesized to both determine the best electrophilic groups for inhibitors and serve as tools for the development of a click chemistry fluorescence assay for evaluating covalent labeling. Following incubation of the probes with the LuxS enzyme, an azide-conjugated dye will be utilized to detect covalent binding.

Synthesis toward inhibitors of quorum sensing enzyme LuxS

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