Teichoic acids (TA) are copolymers of glycerol phosphate or ribitol phosphate and carbohydrates linked via phosphodiester bonds. Teichoic acids are found within the cell wall of most Gram-positive bacteria, which make them potential antibiotic targets for Gram-positive bacteria. Creative Biolabs has developed a top drug discovery platform to identify novel antibacterial drug targets related to teichoic acid.
Figure 1. Teichoic acid synthesis
Except for peptidoglycan, Gram-positive bacteria are comprised of a second, equally abundant component: teichoic acid. Teichoic acid is comprised of linear, polyol phosphate polymers that exist in one of two forms: wall teichoic acid (WTA) attached to wall peptidoglycan, and lipoteichoic acid (LTA) linked to membrane lipids. Creative Biolabs' professional drug discovery group has the ability to identify targets related to both wall teichoic acid and lipoteichoic acid for our clients.
Wall Teichoic Acid (WTA)
WTAs are the most abundant PG-linked polymers in many Gram-positive organisms. WTAs are involved in many aspects of cell division and are essential for maintaining cell shape in rod-shaped organisms. Due to their importance in pathogenesis, WTAs are potential targets for new therapeutics to overcome bacterial infections. The WTA pathway contains three distinct target categories: antivirulence targets, β-lactam potentiator targets, and essential targets.
Figure 2. Wall teichoic acid biosynthetic enzymes are potential antibiotic targets. (Brown et.al. 2013)
Virulence Targets
It is worth investigating virulence factor targets, particularly for resistant pathogens. Enzymes of the Dlt operon are targets for antivirulence agents since strains lacking TA D-alanine esters are strongly attenuated in vivo. Except Dlt, the enzymes involved in initiating WTA polymer synthesis, TarO, and TarA, have also been described as virulence factor targets.
β-lactam Potentiator Targets
β-lactam are one of the safest and most widely used classes of antibiotics, and there is considerable interest in compounds that restore β-lactam sensitivity to resistant microorganisms. TarO, TarA, and TarS enzymes related with WTA synthesis are β-lactam potentiator targets. Through cell-based high throughput β-lactam potentiation screen, we will identify β-lactam potentiator targets on WTA.
Late Stage WTA Pathway Inhibitors
Inhibitors of the WTA biosynthetic enzymes TarB have lethal effects on bacterial cells and would be akin to traditional antibiotics. By screening a ΔtarO mutant and a wild-type strain against the same library, we could discover late stage WTA pathway inhibitors.
Lipoteichoic Acid (LTA)
Lipoteichoic acid (LTA) is an alditol phosphate-containing polymer that is linked via a lipid anchor to the outside of the membrane in Gram-positive bacteria. LTA plays an important role in bacterial growth and physiology and contributes to membrane homeostasis. It is an attractive target for vaccines and novel antimicrobials.
Figure 3. Teichoic acid assembly (Pasquina et.al. 2013)
Despite structural similarities, LTA and WTA are synthesized in different pathways. LTA are polymerized by LtaAS on a lipid anchor on the outer leaflet of the plasma membrane. Among the enzymes in the LTA biosynthetic pathway, LtaA and LtaS appear to be promising as they are exposed to the extracellular milieu and have no human homologs. By our abundant compound libraries and professional group, we could screen inhibitors targeting on LTA biosynthesis for our clients.
Creative Biolabs' professional group has the ability to identify novel antibacterial drug targets in cell wall targets. For more detailed information, please feel free to contact us or directly sent us an inquiry.
References
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