8FK2

The N-terminal VicR from Streptococcus mutans

Summary for 8FK2

• Entry DOI: 10.2210/pdb8fk2/pdb
• Descriptor: Putative response regulator CovR VicR-like protein (2 entities in total)
• Functional Keywords: gene regulator, gene regulation
• Biological source: Streptococcus mutans UA159
• Total number of polymer chains: 2
• Total formula weight: 27583.67

Authors

Zhang, H.,Wu, H. (deposition date: 2022-12-20, release date: 2023-10-25)

Primary citation

Liu, C.,Zhang, H.,Peng, X.,Blackledge, M.S.,Furlani, R.E.,Li, H.,Su, Z.,Melander, R.J.,Melander, C.,Michalek, S.,Wu, H.
Small Molecule Attenuates Bacterial Virulence by Targeting Conserved Response Regulator.
Mbio, 14:e0013723-e0013723, 2023

PubMed Abstract: Antibiotic tolerance within a biofilm community presents a serious public health challenge. Here, we report the identification of a 2-aminoimidazole derivative that inhibits biofilm formation by two pathogenic Gram-positive bacteria, Streptococcus mutans and Staphylococcus aureus. In S. mutans, the compound binds to VicR, a key response regulator, at the N-terminal receiver domain, and concurrently inhibits expression of and VicR-regulated genes, including the genes that encode the key biofilm matrix producing enzymes, Gtfs. The compound inhibits S. aureus biofilm formation via binding to a Staphylococcal VicR homolog. In addition, the inhibitor effectively attenuates S. mutans virulence in a rat model of dental caries. As the compound targets bacterial biofilms and virulence through a conserved transcriptional factor, it represents a promising new class of anti-infective agents that can be explored to prevent or treat a host of bacterial infections. Antibiotic resistance is a major public health issue due to the growing lack of effective anti-infective therapeutics. New alternatives to treat and prevent biofilm-driven microbial infections, which exhibit high tolerance to clinically available antibiotics, are urgently needed. We report the identification of a small molecule that inhibits biofilm formation by two important pathogenic Gram-positive bacteria, Streptococcus mutans and Staphylococcus aureus. The small molecule selectively targets a transcriptional regulator leading to attenuation of a biofilm regulatory cascade and concurrent reduction of bacterial virulence . As the regulator is highly conserved, the finding has broad implication for the development of antivirulence therapeutics that selectively target biofilms.

PubMed: 37074183
DOI: 10.1128/mbio.00137-23

Experimental method

X-RAY DIFFRACTION (2.29 Å)