In Silico Selection and In Vitro Evaluation of New Molecules That Inhibit the Adhesion of Streptococcus mutans through Antigen I/II

Abstract

Streptococcus mutans is the main early colonizing cariogenic bacteria because it recognizes salivary pellicle receptors. The Antigen I/II (Ag I/II) of S. mutans is among the most important adhesins in this process, and is involved in the adhesion to the tooth surface and the bacterial co-aggregation in the early stage of biofilm formation. However, this protein has not been used as a target in a virtual strategy search for inhibitors. Based on the predicted binding affinities, drug-like properties and toxicity, molecules were selected and evaluated for their ability to reduce S. mutans adhesion. A virtual screening of 883,551 molecules was conducted; cytotoxicity analysis on fibroblast cells, S. mutans adhesion studies, scanning electron microscopy analysis for bacterial integrity and molecular dynamics simulation were also performed. We found three molecules ZINC19835187 (ZI-187), ZINC19924939 (ZI-939) and ZINC19924906 (ZI-906) without cytotoxic activity, which inhibited about 90% the adhesion of S. mutans to polystyrene microplates. Molecular dynamic simulation by 300 nanoseconds showed stability of the interaction between ZI-187 and Ag I/II (PDB: 3IPK). This work provides new molecules that targets Ag I/II and have the capacity to inhibit in vitro the S. mutans adhesion on polystyrene microplates.

Cross-kingdom interaction between Candida albicans and oral bacteria

“…Furthermore, recombinantly expressed human and mouse serum amyloid A1 (rhSAA1) proteins promote cell aggregation and target the C. albicans cell wall adhesin Als3 ( Gong et al, 2020 ). Computational methodologies have become crucial components of many programs used in pharmaceutical production for discovery of new antibacterial targets that may decrease virulence of cariogenic microorganisms present in dental biofilms and quickly predict their spectrum and selectivity ( da Silva et al, 2014 ; Rivera-Quiroga et al, 2020 ; Alharbi et al, 2022 ). Indeed, we still have a long way to go in finding effective treatments.…”

Proteomics of Streptococcus mutans to Reveal the Antibiofilm Formation Mechanism of Ag/ZnO Nanocomposites with Light-Emitting Diode Radiation

“…A0A0A0R886 and A0A0A0RAT8 were found to be upregulated, as they are responsible for the sucrose-independent initial adhesion process. 35 , 46 In addition to those membrane proteins, the differentially expressed proteins in macromolecular complexes and organelles were reported to be related to DNA replication (DNA polymerase III ( SMU29_09019 )), transcription (MepR ( mepR ) 47 ), and translation ( rplL, rpmG , and tsf 48 ). Using GO enrichment analysis, the top three terms in the cellular component terms were extracellular region, cell wall, and external encapsulating structure.…”

“… 54 Herein, the reductions in adhesion and EPS shown in Figure 3A and B were explained by the up- or downregulation of glucan-binding protein A ( SMU82_00485 ), gbpD , glucan-binding protein C ( SMU82 _ 05402 ), glucosyltransferase-SI (fragment) ( SMU82 _ 09792 ), and gtfC . In addition, several other biofilm-related proteins were mentioned above, including two PAs (A0A0A0R886 and A0A0A0RAT8), 35 , 46 tsf , 36 and srtA . 44 The notable proteomic changes shown in the heat map in Figure 5E demonstrated the multiple antibiofilm formation actions of the synergistic therapy against S. mutans .…”

The Application of Small Molecules to the Control of Typical Species Associated With Oral Infectious Diseases

“…Antigen I/II, also known as Pac, mediates the sucrose-independent adhesion of S. mutans (Munro et al, 1993;Jenkinson and Demuth, 1997;Love et al, 1997), while Gtfs (GtfB, GtfC, and GtfD) mediate its sucrose-dependent adhesion (Bramstedt, 1968) and play an important role in the interspecies coaggregation and the development of oral biofilms (Bowen and Koo, 2011;. Rivera-Quiroga et al performed a high-throughput screening of 883551 molecules, and identified three molecules, namely ZINC19835187 (ZI-187), ZINC19924939 (ZI-939) and ZINC 19924906 (ZI-906), which targeted antigen I/II and inhibited the adhesion of S. mutans with low cytotoxicity (Rivera-Quiroga et al, 2020). Wu et al also screened and identified a molecule called 2A4, showing selectivity on S. mutans in multispecies biofilms via inhibiting antigens I/II and Gtfs (Liu et al, 2011).…”

“…Rivera-Quiroga et al. performed a high-throughput screening of 883551 molecules, and identified three molecules, namely ZINC19835187 (ZI-187), ZINC19924939 (ZI-939) and ZINC 19924906 (ZI-906), which targeted antigen I/II and inhibited the adhesion of S. mutans with low cytotoxicity ( Rivera-Quiroga et al., 2020 ). Wu et al.…”