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.
Highlights
Bacterial Biofilms and Human HealthBiofilms are sessile multicellular bacterial communities encased in a three-dimensional meshwork formed by extracellular polymeric substances (EPSs) (Roy et al, 2018)
Since the inhibitors can be structurally similar to the substrate guanosine triphosphate (GTP), a caveat of this approach is that they might interfere with other GTP-involved metabolic pathways in bacteria or host cells
(3) Chemical modification of backbone molecules similar to the structure of cdi-GMP. c-di-GMP analogs can be degraded by PDEs
Summary
Biofilms are sessile multicellular bacterial communities encased in a three-dimensional meshwork formed by extracellular polymeric substances (EPSs) (Roy et al, 2018). C-di-GMP Signaling Systems Control Bacterial Biofilm Formation c-di-GMP (bis-(3′-5′)-cyclic dimeric guanosine monophosphate or cyclic diguanylate monophosphate) is one of dinucleotide second messengers in bacteria. It was discovered in 1987 while researchers were studying cellulose synthesis in Gluconoacetobacter xylinus (Ross et al, 1987). The chemical 2′-F-c-di-GMP (Figure 2B) binds to the I-site, and IC50 was 11 μM when it was tested with WspR, a DGC of P. aeruginosa This chemical inhibits PDEs, and the inhibitory activity against PDEs is stronger than that against the DGC, which could increase the cellular concentration of c-di-GMP. The PleD activity with 100 μM of DC1058 and 100 μM of GTP is ∼32% of that without
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