Quorum quenching agents: resources for antivirulence therapy

Abstract

The continuing emergence of antibiotic-resistant pathogens is a concern to human health and highlights the urgent need for the development of alternative therapeutic strategies. Quorum sensing (QS) regulates virulence in many bacterial pathogens, and thus, is a promising target for antivirulence therapy which may inhibit virulence instead of cell growth and division. This means that there is little selective pressure for the evolution of resistance. Many natural quorum quenching (QQ) agents have been identified. Moreover, it has been shown that many microorganisms are capable of producing small molecular QS inhibitors and/or macromolecular QQ enzymes, which could be regarded as a strategy for bacteria to gain benefits in competitive environments. More than 30 species of marine QQ bacteria have been identified thus far, but only a few of them have been intensively studied. Recent studies indicate that an enormous number of QQ microorganisms are undiscovered in the highly diverse marine environments, and these marine microorganism-derived QQ agents may be valuable resources for antivirulence therapy.

Figure 1

Structures of representative quorum sensing (QS) signals.

Figure 2

Representative QS circuits and autoinducer biosynthesis. (a) LuxI/R circuit of Vibrio fischeri. OM: outer membrane. IM: inner membrane; (b) QS circuit of V. harveyi; (c) Biosynthesis of N-acylhomoserine lactones (AHLs), V. cholerae autoinducer-1 (CAI-1) analogs and 4,5-dihydroxy-2,3-pentanedione (DPD). Differently colored carbons, nitrogens and oxygens show where they are derived. See details in the text.

Figure 3

Neighbour-joining tree of N-acylhomoserine lactone (AHL) enzymes based on amino acid sequences. Each of these AHL lactonases was experimentally identified, except the members named with accession number in Genbank (bold). MomL, MomA and Murru 3261 were identified by us recently (blue colored). The dendrogram was constructed by neighbor-joining method with the MUSCLE program in the MEGA software package (1000 bootstrap replicates). Bootstrap coefficients below 50% were not shown. Scale bar, 0.1 substitutions per amino acid position. Marine clusters were colored in blue. (a) Tree of AHL lactonase; (b) tree of acylase. ND: not determined.