Acyl Homoserine Lactone Analogs as Potential Inhibitors of Quorum Sensing

Gram negative bacteria are difficult to treat and are becoming increasingly resistant to conventional antibiotics. Pseudomonas aeruginosa is one such bacterium that causes opportunistic infections in hospital settings and has been recognized by the CDC and WHO as a looming threat to public health due to few treatment options and the rise of antibiotic resistance. A promising strategy to combat antibiotic resistance is to focus on virulence, rather than growth. In an antivirulence approach, the goal is to compromise the bacterium's pathogenicity so that it is easier for the host's immune system to clear the infection. Many Gram negative bacteria like P. aeruginosa and Chromobacterium violaceum use a LuxIR quorum sensing system to control virulence, where the LuxI synthase makes an acyl homoserine lactone signal that is detected by the LuxR transcriptional regulator, leading to the upregulation of virulence genes. One way to block virulence is to disrupt the production of the quorum sensing signaling molecules. In this study we have designed, synthesized and structurally characterized a series of potential small molecule inhibitors of the CviI synthase from C. violaceum as a model system for the more complex P. aeruginosa system. CviI converts a hexanoyl-acyl carrier protein (hexanoyl-ACP) and S-adenosylmethionine (SAM) to a C6-homoserine lactone (C6-HSL). The potential inhibitors were designed to mimic the structural moieties of the acyl-ACP starting material and the C6-HSL product. The appropriate chain length should give specificity for the CviI synthase over other LuxI homologs. By varying the head group, the hope is to find an inhibitor that maximizes the affinity for the acyl-ACP binding pocket, inhibiting the enzyme from making the C6-HSL signal. An advantage of our methodology is that the synthesis only requires one step, which enables a quick production of a library to elucidate structure-activity relationships. In future experiments, these compounds will be assayed in C. violaceum to determine if they possess anti-quorum sensing and, specifically, anti-CviI activity. The information gained could serve as a guide for future quorum sensing inhibitor development for P. aeruginosa and other Gram negative pathogens.