Quorum-quenching microbial infections: mechanisms and implications

Abstract

The discovery of antibiotics early in the past century marked the beginning of active control and prevention of infectious microbial diseases. However, extensive use of antibiotics has also unavoidably resulted in the emergence of ‘superbugs’ that resist conventional antibiotics. The finding that many pathogens rely on cell-to-cell communication mechanisms, known as quorum sensing, to synchronize microbial activities essential for infection and survival in the host suggests a promising disease control strategy, i.e. quenching microbial quorum sensing or in short, quorum quenching. Work over the past few years has demonstrated that quorum-quenching mechanisms are widely conserved in many prokaryotic and eukaryotic organisms. These naturally occurring quorum-quenching mechanisms appear to play important roles in microbe–microbe and pathogen–host interactions and have been used, or served as lead compounds, in developing and formulating a new generation of antimicrobials. Characterization of the crystal structures of several types of quorum-quenching enzymes has provided valuable information to elucidate the catalytic mechanisms, as well as clues for future protein tailoring and molecular improvement. The discovery of quorum-sensing signal degradation enzymes in mammalian species represents a new milestone in quorum sensing and quorum quenching research. The finding highlights the importance of investigating their roles in host innate defence against infectious diseases and to determine the factors influencing their in vivo concentrations and catalytic activities.

Figure 1

Examples of microbial quorum-sensing signals. The information was summarized from the following references: Hornby et al. (2001), Zhang & Dong (2004) and Waters & Bassler (2005). A range of AHL signals with variation in acyl chain (n=0, 1, 2, …; R=H, O or OH) have been identified in over 70 Gram-negative bacterial species.

Figure 2

Two general mechanisms of microbial quorum sensing. (a) Signal detection by a cytosolic transcription factor, represented by the AHL-type quorum-sensing system. The signals produced by a LuxI-type protein (I) accumulate in intercellular environment, transport into cytosol, bind to LuxR-type transcription factors (R), and initiate expression of the target genes (indicated by dashed lines). (b) Signal detection by a two-component sensor and response regulator pair, represented by the AIP-type quorum-sensing system. Precursor peptides (PP) are modified and the resulting AIP signals exported by an ABC transporter (T). The signals are detected by the sensor histidine kinase (S), transduced to the cognate response regulator (RR) by phosphorylation relay (P), which modulates the target gene expression.

Figure 3

Synthesis and degradation of AHL-type signals. (a) I-protein catalyses biosynthesis of AHL signal using substrates acyl-ACP and SAM. (b) AHL degradation by AHL-lactonase, PONs and AHL-acylase.