Exploiting quorum sensing to confuse bacterial pathogens

Abstract

Cell-cell communication, or quorum sensing, is a widespread phenomenon in bacteria that is used to coordinate gene expression among local populations. Its use by bacterial pathogens to regulate genes that promote invasion, defense, and spread has been particularly well documented. With the ongoing emergence of antibiotic-resistant pathogens, there is a current need for development of alternative therapeutic strategies. An antivirulence approach by which quorum sensing is impeded has caught on as a viable means to manipulate bacterial processes, especially pathogenic traits that are harmful to human and animal health and agricultural productivity. The identification and development of chemical compounds and enzymes that facilitate quorum-sensing inhibition (QSI) by targeting signaling molecules, signal biogenesis, or signal detection are reviewed here. Overall, the evidence suggests that QSI therapy may be efficacious against some, but not necessarily all, bacterial pathogens, and several failures and ongoing concerns that may steer future studies in productive directions are discussed. Nevertheless, various QSI successes have rightfully perpetuated excitement surrounding new potential therapies, and this review highlights promising QSI leads in disrupting pathogenesis in both plants and animals.

Fig 1

Simplified schemes of five quorum-sensing networks. Primary synthases, receptors, and other regulatory proteins are arranged around each cell to illustrate regulatory pathways. Arrows imply information flow, whereas T-bars indicate negative regulation. Arrows labeled “+” indicate documented positive feedback. LuxN and LuxM are unique to Vibrio harveyi, as indicated with the subscript ‘vh’ in panel C.

Fig 2

Structures of selected QS signal molecules.

Fig 3

Mechanistic actions of AHL lactonase and AHL acylase enzymes. Dashed lines in the AHL schematic indicate the site of bond cleavage by lactonase (A) or acylase (B).

Fig 4

Lactonase AiiA expression in plants inhibits virulence effects of Erwinia carotovora. E. carotovora was inoculated onto leaves of tobacco (a and b) or potato tuber slices (c), transformed with an aiiA expression vector (top row) or untransformed (bottom row). The extent of tissue maceration was measured at 20 h (a), 40 h (b), and 48 h (c). (Adapted from reference with permission of MacMillan Publishers Ltd.)

Fig 5

Venn diagrams showing “degenerate” AHL analogues tested for activity on LasR, TraR, LuxR, and QscR. Overlapping regions indicate ligands with notable activity in two or more receptors. (Reprinted from reference . Copyright 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany.)

Fig 6

Inhibition of Staphylococcus aureus agr quorum sensing. Activation of the agr system can be visualized with an agrp₃-luxABCDE reporter (column 2) and is required for hemolysin activity on blood agar plates (column 3) and lesion formation in a subcutaneous infection model in mice (column 4) (compare each to the first row, where agr is mutated). The effect of AIP-II on the agr-I strain phenocopies the agr mutant, demonstrating inhibition of agr signaling. (Reprinted from reference . Copyright 2005 National Academy of Sciences, U.S.A.)

Fig 7

Induction (a) and inhibition (b) of violacein synthesis in Chromobacterium violaceum CV026 by synthetic AHLs. (a) CV026 seeded in agar; (b) CV026 plus 1 μM C6HSL. Various AHL compounds, numbered 1 to 11, were added to wells cut into the agar. Violacein production (dark halos around wells in panel a) indicates agonistic activity, and white halos (b) indicate violacein inhibition and hence AHL antagonism. (Reprinted from reference with permission of the Society for General Microbiology.)