Bacterial glucosyltransferase (GTF)

Bacterial glucosyltransferases (GTFs) are a diverse family of enzymes that play pivotal roles in bacterial physiology and pathogenesis, serving as key targets for both traditional antibiotics and novel anti-virulence strategies [6, 15]. In the context of oral health, GTFs from Streptococcus mutans (specifically GtfB, GtfC, and GtfD) are essential virulence factors that catalyze the synthesis of extracellular polysaccharides (glucans) from dietary sucrose [20, 26]. These glucans provide the structural scaffold for dental plaque biofilms, enabling bacterial adhesion to tooth enamel and protecting the microbial community from environmental stressors and antimicrobial agents [7, 33]. Another therapeutically significant class is the peptidoglycan glycosyltransferases (also known as transglycosylases), which are responsible for the polymerization of the bacterial cell wall and are the primary target of the natural product moenomycin [2, 29]. Targeting GTFs is considered a promising pathoblocker approach, as inhibiting these enzymes can reduce bacterial colonization and biofilm formation without necessarily killing the bacteria, thereby potentially minimizing the selective pressure for antibiotic resistance [14, 25]. While several experimental inhibitors, such as quinoxaline derivatives, G43, and various plant-derived polyphenols, have demonstrated efficacy in preclinical models of dental caries, no GTF-specific inhibitors have yet reached clinical approval for human use [23, 24, 28]. The structural distinctness of bacterial GTFs from human glycosyltransferases makes them attractive for drug development, although challenges remain regarding the bioavailability and selectivity of small-molecule candidates [5, 31, 34].

Other names

GlucansucraseDextransucraseSucrose:1,6-alpha-D-glucan 6-alpha-D-glucosyltransferasePeptidoglycan glycosyltransferaseTransglycosylaseGtfBGtfCGtfD

Bacterial glucosyltransferases are targeted through several mechanisms: (1) competitive or non-competitive inhibition of the catalytic domain to prevent the polymerization of glucose into glucans from a sucrose substrate [4, 8, 20, 33]; (2) inhibition of the transglycosylase activity of penicillin-binding proteins (PBPs) to block the elongation of peptidoglycan chains [2, 3, 5, 34]; and (3) modulation of gene expression or enzyme secretion to reduce the availability of the enzyme in the extracellular environment [24, 33].