Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar‐Based Molecules that Target Bacterial Glucosyltransferase

Hartman, Alwin M.; Jumde, Varsha R.; Elgaher, Walid A. M.; Poele, Evelien M. te; Dijkhuizen, Lubbert; Hirsch, Anna K. H.

doi:10.1002/cmdc.202000222

Cited by 8 publications

(7 citation statements)

References 49 publications

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“…64 Computer-aided structure-based drug designs guide the development and optimization of lead compounds to increase their affinity, and pharmacodynamic and pharmacokinetic properties. 65 Strategies employing the in silico methods can be used to predict drug toxicity early on in the drug discovery process, which should facilitate the development of more effective and selective inhibitors.…”

Section: Reducing the Gtfs Enzymatic Activitiesmentioning

confidence: 99%

Molecular mechanisms of inhibiting glucosyltransferases for biofilm formation in Streptococcus mutans

Zhang

Wang

et al. 2021

Int J Oral Sci

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Glucosyltransferases (Gtfs) play critical roles in the etiology and pathogenesis of Streptococcus mutans (S. mutans)- mediated dental caries including early childhood caries. Gtfs enhance the biofilm formation and promotes colonization of cariogenic bacteria by generating biofilm extracellular polysaccharides (EPSs), the key virulence property in the cariogenic process. Therefore, Gtfs have become an appealing target for effective therapeutic interventions that inhibit cariogenic biofilms. Importantly, targeting Gtfs selectively impairs the S. mutans virulence without affecting S. mutans existence or the existence of other species in the oral cavity. Over the past decade, numerous Gtfs inhibitory molecules have been identified, mainly including natural and synthetic compounds and their derivatives, antibodies, and metal ions. These therapeutic agents exert their inhibitory role in inhibiting the expression gtf genes and the activities and secretion of Gtfs enzymes with a wide range of sensitivity and effectiveness. Understanding molecular mechanisms of inhibiting Gtfs will contribute to instructing drug combination strategies, which is more effective for inhibiting Gtfs than one drug or class of drugs. This review highlights our current understanding of Gtfs activities and their potential utility, and discusses challenges and opportunities for future exploration of Gtfs as a therapeutic target.

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Section: Reducing the Gtfs Enzymatic Activitiesmentioning

confidence: 99%

Molecular mechanisms of inhibiting glucosyltransferases for biofilm formation in Streptococcus mutans

Zhang

Wang

et al. 2021

Int J Oral Sci

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“…This concentration is higher than previously reported 15 , mainly because a drop in effectiveness was expected with the substitutions proposed here. Acarbose was used as a control, given that this molecule was used to resolve the crystallographic structure of GTF-C, and therefore, interacts with the active site of the enzyme in computational models 16 – 18 . However, its effects as a true biofilm inhibitor are underexplored.…”

Section: Methodsmentioning

confidence: 99%

The potential use of glycosyl-transferase inhibitors for targeted reduction of S. mutans biofilms in dental materials

Scaffa

Kendall

Icimoto

et al. 2023

Sci Rep

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Streptococcus mutans is the primary oral caries-forming bacteria, adept at producing “sticky” biofilms via the synthesis of insoluble extracellular polysaccharides (EPS), catalyzed by glucosyltransferases (GTFs). To circumvent the use of broad-spectrum antibiotics to combat these bacteria, this study sought to modify existing EPS-targeting small molecules with the ultimate goal of producing anti-biofilm polymer surfaces specifically targeting S. mutans. To achieve this, a known GTF inhibitor (G43) was modified with methoxy or tetraethyleneglycol substitutions in different positions (nine derivatives, tested at 50-µM) to pinpoint potential sites for future methacrylate functionalization, and then assessed against single-species S. mutans biofilms. As expected, the compounds did not diminish the bacterial viability. In general, the compounds with methoxy substitution were not effective in reducing EPS formation, whereas the tetraethyleneglycol substitution (G43-C3-TEG) led to a decrease in the concentration of insoluble EPS, although the effect is less pronounced than for the parent G43. This aligns with the reduced GTF-C activity observed at different concentrations of G43-C3-TEG, as well as the consequent decrease in EPS formation, and notable structural changes. In summary, this study determined that G43-C3-TEG is non-bactericidal and can selectively reduce the biofilm formation, by decreasing the production of EPS. This molecule will serve to functionalize surfaces of materials to be tested in future research.

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“…From the outcome of the DCL, the rationally synthesized glucose-based hits 101 ( K d = 1.6 mM) with low binding affinity and compound 102 ( K d = 0.4 mM) with moderate binding affinity were identified as the best GTF 180 ligands (Figure ). This work demonstrates the utility of DCC to find out the ligands in the absence of known ligand for the notoriously challenging target with weak ligand interaction and affinity such as sugar-converting enzymes.…”

Section: Synthetic Carbohydrate-based Potent Antibiofilm Agentsmentioning

confidence: 99%

Small Carbohydrate Derivatives as Potent Antibiofilm Agents

Singh

Kulkarni

2022

J. Med. Chem.

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Biofilm formation by most pathogenic bacteria is considered as one of the key mechanisms associated with virulence and antibiotic resistance. Biofilm-forming bacteria adhere to the surfaces of biological or implant medical devices and create communities within their self-produced extracellular matrix that are difficult to treat by existing antibiotics. There is an urgent need to synthesize and screen structurally diverse molecules for their antibiofilm activity that can remove or minimize the bacterial biofilm. The development of carbohydrate-based small molecules as antibiofilm agents holds a great promise in addressing the problem of the eradication of biofilm-related infections. Owing to their structural diversity and specificity, the sugar scaffolds are valuable entities for developing antibiofilm agents. In this perspective, we discuss the literature pertaining to carbohydrate-based natural antibiofilm agents and provide an overview of the design, activity, and mode of action of potent synthetic carbohydrate-based molecules.

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Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar‐Based Molecules that Target Bacterial Glucosyltransferase

Cited by 8 publications

References 49 publications

Molecular mechanisms of inhibiting glucosyltransferases for biofilm formation in Streptococcus mutans

Molecular mechanisms of inhibiting glucosyltransferases for biofilm formation in Streptococcus mutans

The potential use of glycosyl-transferase inhibitors for targeted reduction of S. mutans biofilms in dental materials

Small Carbohydrate Derivatives as Potent Antibiofilm Agents

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