Synthesis and Activity of Oxetane Analogs to Molecules in Bacterial Quorum Sensing

Abstract

Quorum sensing signalling pathways allow bacteria to modulate certain behaviors such as biofilm formation and the secretion of virulence factors. Gram-negative bacteria such as Pseudomonas aeruginosa use N-acyl homoserine lactones (AHLs) as quorum sensing signalling molecules, which consist of a lactone head group and an acyl tail group. Modifying these head groups and tail groups in certain ways has been shown to modulate quorum sensing activity in model bacteria. Such modulations could be important to attenuating bacterial virulence in human pathogens. A modification that has not yet been reported in literature is one where an oxetane ring takes the place of the carbonyl in the lactone head group. The oxetane group is thought to be an isostere for the carbonyl group, and thought to be more stable in vivo than the lactone, making its bioactivity potentially very interesting. This study made significant progress in synthesizing the oxetane analog to the AHL head group, suggesting that while challenging, the synthesis of this analog is possible. Although the bioactivity of the head group could not be assayed, the study provides a synthetic outline for pursuing the testing of this activity, and a better understanding of quorum sensing.