Lian-Hui Zhang graduated from the South China Agricultural University in 1982 and received his PhD degree from the University of Adelaide in 1993. He is one of the pioneers in bacterial quorum sensing by discovery of an AHL-type quorum sensing signal essential for Agrobacterium tumefaciens Ti plasmid conjugal transfer in early 1990s. He has been an Australian Research Council Postdoctoral Research Fellow, and has received the NUS Outstanding Researcher Award (2002) and Singapore National Science Award (2005) for his work in quorum sensing and quorum quenching. He moved his laboratory from Australia to Singapore in 1998 and currently he is a Research Director/ Professor in IMCB.

To gain maximal benefit in a competitive environment, single-celled bacteria have adopted a community genetic regulatory mechanism, known as quorum sensing. Bacterial pathogens use quorum sensing signaling systems to synchronize gene expression and coordinate diverse biological functions, including virulence and biofilm development. Investigation of the molecular mechanisms of quorum sensing could have enormous implications in understanding microbial ecology and pathogenesis, and in developing novel approaches to control infectious diseases and biofilm-associated problems.

Quorum sensing bacterial cells produce, detect and respond to small signal molecules to coordinate community behaviors in a population density–dependent manner. Different bacterial pathogens may produce and respond to different quorum sensing signals. One ongoing research interest in Zhang’s group is the identification and characterization of new signaling molecules. The group has completed structural analysis of a diffusible signal factor (DSF) that regulates virulence and biofilm dispersal in Xanthomonas campestris (Fig. 1). DSF was identified as methyl dodecenoic acid, which represents a new class of QS signals that seems to be conserved in a range of bacterial species. More recently, they have identified a DSF analogue from Burkholderia cenocepacia, which has been structurally determined as dodecenoic acid (designated as BDSF). Similar to DSF, BDSF appears to play significant roles in both intraspecies and interspecies communications. Subsequent studies have unveiled the presence of DSF-based QS systems in numerous Gram-negative bacterial species. These QS systems of different bacterial origins may vary in signal chemistry and signaling mechanisms, but their roles in the regulation of virulence and biofilm development are highly conserved. Furthermore, evidence is accumulating that DSF-family signals display high potencies in interspecies and cross kingdom communications, highlighting their significance not only in bacterial physiology but also in microbial ecology.

Another focus of Zhang’s group is the systems biology of microbial quorum sensing. His major curiosities are: (1) signaling and regulatory mechanism; (2) quorum sensing regulon; and (3) quorum sensing regulatory networks. By using genetic and biochemical analysis, the group has unveiled that DSF signal production is auto-regulated by a novel post-translational mechanism, which involves protein-protein interaction between the DSF synthase RpfF and sensor RpfC. By using an integrative genomic and genetic approach, they have further demonstrated that DSF regulates a wide range of genes encoding various biological functions, including virulence, biofilm dispersal, drug resistance and survival competence, through a hierarchical signaling network (Fig. 1). More recently, they have demonstrated that Clp is a novel c-di-GMP effector. Together with their collaborators, they have outlined the DSF signaling mechanism in bacterial pathogen Xanthomonas campestris. Upon detection of DSF signal when bacteria reach a threshold population, autophosphorylation of RpfC triggers phosphorelay through its HK to REC to HPT domains, and subsequently to the REC domain of RpfG. Phosphorylation of RpfG is believed to induce protein conformational changes and activate its phosphodiesterase activity. Degradation of c-di-GMP molecules by the activated RpfG reduces the intracellular level of this second messenger, resulting in increased intracellular level of free Clp, which regulates the target genes expression directly or indirectly through its downstream transcriptional factors including Zur and FhrR (Fig. 1).

Prokaryote-prokaryote and prokaryote-eukaryote interactions are ubiquitous in natural ecosystems. Given that diverse bacterial species use quorum sensing-coordinated community biological activities to boost their competitive advantages, for example, production of antibiotics and virulence factors, it is rational that competitors may have also evolved certain mechanisms to disarm the quorum sensing systems of microbes to gain the upper hand in competition. Prompted by this consideration, Zhang’s group has discovered two types of widely conserved novel enzymes that degrade AHL-type quorum sensing signals (AHL-lactonase and AHL-acylase). Kinetics and specificity analyses show that AHL-lactonase is a potent and highly specific enzyme. By using a transgenic approach, they have demonstrated that it is feasible to prevent and control bacterial infections in a practical way. This strategy is widely known as “quorum quenching”. Similarly, they found that quenching quorum-sensing by inactivation of quorum sensing signal blocks bacterial biofilm formation (Fig. 2). Their latest results indicate that the enzymes that degrades AHL-type QS signals are widely conserved in mammalian species. The group is currently testing the potentials of the quorum quenching enzymes as therapeutical proteins, and will continue to screen and characterize novel signal interference molecules to control and prevent the QS-mediated bacterial and fungal infections and biofilm formation.