Medicinal Chemistry as a Conduit for the Modulation of Quorum Sensing

The evolutionary development of bacterial cell-to-cell communication, a process termed “quorum sensing” (QS), enabled coordinated behavioral efforts of bacterial populations, thus providing for microbial interaction with higher organisms. QS signaling defines the process of bacteria secreting and responding to small diffusible chemical signals, or autoinducers, in a cell density-dependent process.1 As the number of cells, and thus autoinducer concentrations, increase, bacteria synchronize their gene expression to behave as a unified group. These concerted efforts are beneficial to the bacterial population, but often come at the expense of human health, as QS has been shown to regulate functions such as biofilm formation and the expression of virulence factors. Consequently, the modulation of QS has emerged as a prophylactic and therapeutic anti-virulence target of considerable interest.2,3 QS signaling is mediated by autoinducing molecules that can be categorized into three major classes:4–7: i) N-acyl homoserine lactones (AHLs), ii) oligopeptides, and iii) autoinducer-2 (AI-2).8,9 AHLs are produced by many Gram-negative bacterial species, and signals are differentiated by acyl chain length and oxidation patterns. Likewise, oligopeptides, such as staphylococcal auto-inducing peptides (AIPs), are the signals employed by Gram-positive bacteria, and are often chemically posttranslationally modified. Lastly, the AI-2 class of signals is derived from the precursor 4,5-dihydroxy-2,3-pentanedione (DPD) and has been shown to signal in both Gram-positive and –negative bacteria. Because of the shared DPD core of the known AI-2 signaling molecules, and the ubiquity of the DPD synthase in the bacterial kingdom, AI-2 has been suggested as a language of interspecies communication. In addition to these three classes, other small molecules including the Pseudomonas quinolone signal (PQS)10, 3-hydroxypalmitic acid methyl ester11, bradyoxetin12, and (S)-3-hydroxytridecan-4-one13 have also been identified. In general, individual species rely on chemically distinct signals to avoid interspecies cross-talk or interference. However, as discussed in this Perspective, the signals of one species often exert agonistic or antagonistic effects on the QS systems of other species. Three main paradigms have been explored for the development of QS modulators as potential therapeutics: i) interference with the signal synthase, ii) sequestration of the autoinducer, and iii) antagonism of the receptor, with receptor antagonism having received the most attention to date for the discovery of QS modulators. Additionally, other modes of actions, such as prevention of signal secretion or inhibition of downstream signaling events, have also been examined. In this Perspective, we will focus on the third approach towards QS modulators, and review their development from a medicinal chemical perspective with a focus on the methods and rationale used for their discovery and/or design and synthesis. We will discuss agonists as well as antagonists of QS systems, and have included relative potencies (EC50values for agonists and IC50values for antagonists) where given in the original literature. In consideration of these values, it is important to state that strict comparisons may only be applied within a set of analogs examined in a particular assay, largely due to variations in reporter assays used for analog evaluation. Finally, we will discuss studies that have strived to establish QS as a viable target for the development of antimicrobial therapies.