Screening for Diguanylate Cyclase (DGC) Inhibitors Mitigating Bacterial Biofilm Formation

Abstract

The majority of bacteria in the natural environment organize themselves into communal biofilms. Biofilm formation benefits bacteria conferring resistance to harmful molecules (e.g., antibiotics, disinfectants, and host immune factors) and coordinating their gene expression through quorum sensing (QS). A primary signaling molecule promoting bacterial biofilm formation is the universal second messenger cyclic di-GMP. This dinucleotide predominantly controls the gene expression of motility, adhesins, and capsule production to coordinate biofilm formation. Cyclic di-GMP is synthesized by diguanylate cyclases (DGCs) that have a GGDEF domain and is degraded by phosphodiesterases (PDEs) containing either an EAL or an HD-GYP domain. Since high cellular c-di-GMP concentrations are correlated with promoting the ability of bacteria to form biofilms, numerous research endeavors to identify chemicals capable of inhibiting the c-di-GMP synthesis activity of DGCs have been performed in order to inhibit bacterial biofilm formation. This review describes currently identified chemical inhibitors that disturb the activity of DGCs and the methods of screening and assay for their discovery.

Innovation and Application of the Type III Secretion System Inhibitors in Plant Pathogenic Bacteria

“…cholerae due to their impact on the c-di-GMP signaling. These molecules exert their function via binding to c-di-GMP directly, affecting the enzymatic activity of DGCs that synthesize c-di-GMP, or mimicking c-di-GMP as a competitor in bacteria [ 157 , 158 , 159 , 160 ]. However, similar studies have not been reported in plant pathogenic bacteria, and the idea of using small molecules that target c-di-GMP for the management of plant diseases needs to be further evaluated.…”

An Overview of Biological and Computational Methods for Designing Mechanism-Informed Anti-biofilm Agents

“…However, various classes of diguanylate cyclases inhibitors have been developed. These include GTP or c-di-GMP analogs, which inhibit diguanylate cyclases in the active site and an allosteric site, respectively (Cho et al, 2020). Small molecule inhibitors of diguanylate cyclases have also been discovered using high-throughput in vitro and in silico screening (Cho et al, 2020), although activities tend to be modest.…”

“…These include GTP or c-di-GMP analogs, which inhibit diguanylate cyclases in the active site and an allosteric site, respectively (Cho et al, 2020). Small molecule inhibitors of diguanylate cyclases have also been discovered using high-throughput in vitro and in silico screening (Cho et al, 2020), although activities tend to be modest. Stimulating activity of phosphodiesterases has been accomplished using nitric oxide donors such as sodium nitroprusside, leading to dispersal of P. aeruginosa biofilms (Barraud et al, 2006).…”

Strategies and Approaches for Discovery of Small Molecule Disruptors of Biofilm Physiology

“…While the inhibitors discussed are not a comprehensive list, they represent a wide range of diverse biofilm inhibitors with differing methods of discovery and inhibitory targets. As there is a growing interest in biofilms as antimicrobial targets, additional biofilm inhibitors and their known action mechanisms have been discussed in recent reviews, including synthetic biofilm inhibitors such as the phenazine and amino-immidozole inhibitor classes [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”