Small Molecule Inhibitors of AI-2 Signaling in Bacteria: State-of-the-Art and Future Perspectives for Anti-Quorum Sensing Agents

Abstract

Bacteria respond to different small molecules that are produced by other neighboring bacteria. These molecules, called autoinducers, are classified as intraspecies (i.e., molecules produced and perceived by the same bacterial species) or interspecies (molecules that are produced and sensed between different bacterial species). AI-2 has been proposed as an interspecies autoinducer and has been shown to regulate different bacterial physiology as well as affect virulence factor production and biofilm formation in some bacteria, including bacteria of clinical relevance. Several groups have embarked on the development of small molecules that could be used to perturb AI-2 signaling in bacteria, with the ultimate goal that these molecules could be used to inhibit bacterial virulence and biofilm formation. Additionally, these molecules have the potential to be used in synthetic biology applications whereby these small molecules are used as inputs to switch on and off AI-2 receptors. In this review, we highlight the state-of-the-art in the development of small molecules that perturb AI-2 signaling in bacteria and offer our perspective on the future development and applications of these classes of molecules.

New Insights into Autoinducer-2 Signaling as a Virulence Regulator in a Mouse Model of Pneumonic Plague

“…Finally, the high conservation of AI-2 transport mechanisms and signaling pathways in microbes presents a significant opportunity for small-molecule intervention (34). Current inhibitors of AI-2 have unknown activity in in vivo models of disease.…”

Strategies for Silencing Bacterial Communication

“…The activity of these multiple C1-alkyl-DPD derivatives in V. harveyi depended on the assay conditions; they were found to function as either antagonists or synergistic agonists (LaSarre and Federle 2013; Defoirdt et al 2012;Lowery et al 2008). However, carbocyclic analogues of DPD did not display significant quenching activities in S. typhimurium or V. harveyi (Tsuchikama et al 2011;Guo et al 2013). Generally, AI-2 QS antagonists can exhibit two different types of activities being antagonists or synergistic agonists (LaSarre and Federle 2013).…”

“…The development of small molecules capable of inhibiting the AI-2 QS system (interspecies communication) is an attractive approach for prevention of wide-range bacterial behaviours from occurring (LaSarre and Federle 2013;Guo et al 2013). With the concept of molecular mimicking and the goal of identifying antagonist of AI-2 receptor proteins, Wang and co-workers found a few sulphone compounds using highthroughput virtual screening able to antagonise LuxP receptor in V. harveyi (Peng et al 2009;Ni et al 2008a).…”

“…Moreover, MT-DADMe-ImmA and BuT-DADMe-ImmA were also demonstrated as potent non-toxic inhibitors of AI-2 synthesis in the pathogenic E. coli. The major concern related to this approach is that by targeting the MTAN enzyme in AI-2 synthesis, the overexpression of quorum-sensing pathway (or alternative pathways) might overcome the effect of developed MTAN inhibitors (Guo et al 2013). …”

Glycation Reactivity of a Quorum‐Sensing Signaling Molecule

“…[3] Fundamental to AI-2 QS on one hand is DPD’s biosynthetic manufacture and receptors found in over 70 bacteria, yet, a consistent link among DPD signal, receptor, mechanism and target output within this plethora of bacterial species has been lacking. [4] Additional questions on DPD’s cross-species signaling role have also been damped by the view that the luxS gene, which was thought to be dedicated to AI-2 production, also assumes an integral function in the activated methyl cycle.…”