Discovery of Potent Inhibitors of Streptococcus
mutans Biofilm with Antivirulence Activity |
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Authors: | Bhavitavya Nijampatnam Parmanand Ahirwar Piyasuda Pukkanasut Holly Womack Luke Casals Hua Zhang Xia Cai Suzanne M. Michalek Hui Wu Sadanandan E. Velu |
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Affiliation: | †Department of Chemistry, ‡Department of Pathology, and §Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States;∥Department of Integrative Biomedical and Diagnostic Sciences, Oregon Health and Science University, Portland, Oregon 97239, United States |
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Abstract: | Dental caries is a bacterial infectious disease characterized by demineralization of the tooth enamel. Treatment of this disease with conventional antibiotics is largely ineffective as the cariogenic bacteria form tenacious biofilms that are resistant to such treatments. The main etiological agent for dental caries is the bacterium Streptococcus mutans. S. mutans readily forms biofilms on the tooth surface and rapidly produces lactic acid from dietary sucrose. Glucosyl transferases (Gtfs) secreted by S. mutans are mainly responsible for the production of exopolysaccharides that are crucial for the biofilm architecture. Thus, inhibiting S. mutans’ Gtfs is an effective approach to develop selective biofilm inhibitors that do not affect the growth of oral commensals. Herein, we report a library of 90 analogs of the previously identified lead compound, G43, and exploration of its structure activity relationships (SAR). All compounds were evaluated for the inhibition of S. mutans biofilms and bacterial growth. Selected compounds from this library were further evaluated for enzyme inhibition against Gtfs using a zymogram assay and for growth inhibition against oral commensal bacterial species such as Streptococcus gordonii and Streptococcus sanguinis. This study has led to the discovery of several new biofilm inhibitors with enhanced potency and selectivity. One of the leads, IIIF1, showed marked reduction in buccal, sulcal, and proximal caries scores in a rat model of dental caries. |
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Keywords: | Dental caries Streptococcus mutans biofilm glucosyl transferases SAR in vivo |
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