Quorum sensing is a type of bacterial cell-to-cell communication, and it is achieved through the production, release and detection of small signaling molecules called autoinducers (AIs). There are two major types of AIs, AI-1 and AI-2. AI-1 includes acylated homoserine lactones and modified peptides, which serve as intra-species signaling molecules. AI-2 is a furanosyl borate diester, a byproduct in the activated methyl cycle of bacteria. AI-2 is an interspecies signaling molecule, which is shared by both gram-negative and gram-positive bacteria. LuxS, S-Ribosylhomocysteinase, is a key enzyme in the biosynthesis of AI-2. The LuxS-dependent quorum sensing systems regulate a diverse array of physiological and pathological activities in bacteria, such as virulence factor expression and biofilm formation. LuxS proteins are well conserved, and its orthologs have been found in over 55 bacterial species, but absent in human. Due to these features, LuxS can be a potential molecular target for developing a novel class of antibiotic agents. Human oral microbial-plaques are biofilms composed of numerous genetically distinct types of bacteria that live in close juxtaposition on host surfaces. Growth as biofilms is essential for oral bacteria to adapt and thrive in oral flora and cause oral infections. Numerous studies have shown that the LuxS- dependent QS systems play very important roles in many oral bacteria in terms of biofilm formation, and production of virulence factors. Thus, LuxS can be a potential target for developing therapeutic agents to prevent or treat periodontal diseases. The goal of this application is to develop LuxS-based therapeutic compounds that specifically inhibit the biofilm formation of pathogenic oral bacteria such as Pg. To achieve this goal, the current application focuses on the following specific aims: (1) To elucidate the biochemical and structural features of LuxS proteins of Sg and Pg;(2) To design and screen specific compounds that inhibit the activity of Pg LuxS in vitro;and (3) To screen the compounds that specifically inhibit the biofilm formation of Pg but not Sg. The accomplishment of these studies will not only lead to a better understanding the biochemical and structural features of LuxS proteins from oral bacteria, but could also provide new means of prevention and treatment of periodontal diseases.
Periodontal infections are caused by a group of oral bacteria that grow as biofilms (plaque) in oral flora. Growth as biofilms is essential for oral bacteria to adapt and thrive in oral flora and cause the infections. The goal of this application is to develop inhibitors that are able to inhibit the biofilm formation of oral bacteria.
|Amano, A; Chen, C; Honma, K et al. (2014) Genetic characteristics and pathogenic mechanisms of periodontal pathogens. Adv Dent Res 26:15-22|
|Qian, Ziqing; LaRochelle, Jonathan R; Jiang, Bisheng et al. (2014) Early endosomal escape of a cyclic cell-penetrating peptide allows effective cytosolic cargo delivery. Biochemistry 53:4034-46|
|Kurniyati, Kurni; Zhang, Weiyan; Zhang, Kai et al. (2013) A surface-exposed neuraminidase affects complement resistance and virulence of the oral spirochaete Treponema denticola. Mol Microbiol 89:842-56|
|Bian, Jiang; Liu, Xiangyang; Cheng, Yi-Qiang et al. (2013) Inactivation of cyclic Di-GMP binding protein TDE0214 affects the motility, biofilm formation, and virulence of Treponema denticola. J Bacteriol 195:3897-905|
|Zhang, Kai; Tong, Brian A; Liu, Jun et al. (2012) A single-domain FlgJ contributes to flagellar hook and filament formation in the Lyme disease spirochete Borrelia burgdorferi. J Bacteriol 194:866-74|
|Bian, Jiang; Fenno, J Christopher; Li, Chunhao (2012) Development of a modified gentamicin resistance cassette for genetic manipulation of the oral spirochete Treponema denticola. Appl Environ Microbiol 78:2059-62|
|Li, Chen; Kurniyati; Hu, Bo et al. (2012) Abrogation of neuraminidase reduces biofilm formation, capsule biosynthesis, and virulence of Porphyromonas gingivalis. Infect Immun 80:3-13|
|Bian, Jiang; Li, Chunhao (2011) Disruption of a type II endonuclease (TDE0911) enables Treponema denticola ATCC 35405 to accept an unmethylated shuttle vector. Appl Environ Microbiol 77:4573-8|
|Malladi, Venkata L A; Sobczak, Adam J; Meyer, Tiffany M et al. (2011) Inhibition of LuxS by S-ribosylhomocysteine analogues containing a [4-aza]ribose ring. Bioorg Med Chem 19:5507-19|
|Bian, Jiang; Shen, Hongwu; Tu, Youbin et al. (2011) The riboswitch regulates a thiamine pyrophosphate ABC transporter of the oral spirochete Treponema denticola. J Bacteriol 193:3912-22|