Chemical methods to interrogate bacterial quorum sensing pathways

Abstract

Bacteria frequently manifest distinct phenotypes as a function of cell density in a phenomenon known as quorum sensing (QS). This intercellular signalling process is mediated by “chemical languages comprised of low-molecular weight signals, known as” autoinducers, and their cognate receptor proteins. As many of the phenotypes regulated by QS can have a significant impact on the success of pathogenic or mutualistic prokaryotic–eukaryotic interactions, there is considerable interest in methods to probe and modulate QS pathways with temporal and spatial control. Such methods would be valuable for both basic research in bacterial ecology and in practical medicinal, agricultural, and industrial applications. Toward this goal, considerable recent research has been focused on the development of chemical approaches to study bacterial QS pathways. In this Perspective, we provide an overview of the use of chemical probes and techniques in QS research. Specifically, we focus on: (1) combinatorial approaches for the discovery of small molecule QS modulators, (2) affinity chromatography for the isolation of QS receptors, (3) reactive and fluorescent probes for QS receptors, (4) antibodies as quorum “quenchers,” (5) abiotic polymeric “sinks” and “pools” for QS signals, and (6) the electrochemical sensing of QS signals. The application of such chemical methods can offer unique advantages for both elucidating and manipulating QS pathways in culture and under native conditions.

Small Molecule Disruption of Quorum Sensing Cross-Regulation in Pseudomonas aeruginosa Causes Major and Unexpected Alterations to Virulence Phenotypes

“…6,7 Due to their critical role in regulating virulence, QS circuits are particularly attractive targets for such compounds. 8,9 Indeed, several recent reports suggest that anti-QS agents will hold significant promise as resistance-robust drugs. 10–12 …”

Mutational Analysis of the Quorum-Sensing Receptor LasR Reveals Interactions that Govern Activation and Inhibition by Nonlactone Ligands

“…Indeed, the ability to modulate QS with non-native molecules has tremendous implications for artificially disrupting or promoting both pathogenic and mutualistic behavior (Galloway et al, 2012; Galloway et al, 2011; Geske et al, 2008a). The spatial and temporal control afforded by chemical probes can enable a deeper understanding of important microbial phenotypes and possibly have direct therapeutic potential (Bjarnsholt and Givskov, 2007; Clatworthy et al, 2007; Praneenararat et al, 2012). As therapeutics, QS inhibitors have a prospective advantage over traditional antibiotic therapies, since recent sociomicrobiology studies suggest that resistance is likely to spread more slowly to QS inhibitors (that target virulence phenotypes) than to traditional antibiotics (that target growth) (Gerdt and Blackwell, 2014; Mellbye and Schuster, 2011).…”

Dendrimer mediated clustering of bacteria: improved aggregation and evaluation of bacterial response and viability

“…However, adfactors. 8,9 Because these strategies do not compromise microbial viability and survival, the evolutionary pressure imposed hesion of polymers to bacteria surfaces can result in the clustering of these bacteria and the activation of signalling within 17,18 on microbes is much smaller than with conventional antibiotics those clusters. Polymeric materials are now starting to be and hence, resistance is less likely to develop.…”