Lipopolysaccharides (LPS) (also lipoglycans or endotoxins) are a kind of large molecules consisting of a lipid and a polysaccharide. They are important components in the outer membrane of Gram-negative bacteria and can act as antigens that elicit strong immune responses in animals. Creative Biolabs has developed a top-class drug discovery platform to identify novel antibacterial drug targets related to lipopolysaccharide synthesis and transport.
LPS is the major component of the outer membrane (OM) of Gram-negative bacteria. It contributes greatly to the structural integrity of the bacteria, which can protect the membrane from certain kinds of chemical attack. LPS has several properties, which contribute to the efficiency of the OM as a permeability barrier: (1) LPS contains several fully saturated fatty acid side chains. The chains make LPS in a gel-like state, thereby preventing easy access to potentially harmful chemicals. (2) LPS molecules have strong lateral interactions which facilitated by the bridging action of divalent cations. (3) Interactions between LPS and outer membrane protein (OMPs) further complicate access to chemicals. Both LPS synthesis and LPS transport are of crucial importance to Gram-negative bacteria. Creative Biolabs provides professional services to identify potential targets related to LPS synthesis and transport.
LPS Biosynthesis in Gram-negative Bacteria
The first step of LPS biosynthesis (Figure 1) is synthesizing Kdo2-Lipid A, which is the minimal LPS required for growth in most strains. After that, two rounds of acylation are conducted to assemble the core oligosaccharide on Kdo2-Lipid A to becomes Core-Lipid A. Core-Lipid A is proposed to be flipped across the inner membrane (IM) by MsbA, where O-antigen units are attached, before transport to the outer membrane (OM). Currently, there are two proteins involved in the biosynthesis of LPS have been extensively explored as targets for novel therapeutics. The first is LpxC, a zinc-dependent metalloamidase that catalyzes the committed step in the biosynthesis of the lipid A moiety of LPS. The other target is LptD for which depletions mirror its effect on LPS localization. Creative Biolabs will screen suitable hits targeting on LPS biosynthesis including LpxC and LptD.
Figure 1. LPS biosynthesis pathway in E. coli. (Sperandeo et.al. 2009)
The LPS Transport System (Lpt) of Gram-negative Bacteria
A model for LPS transport from the IM to the OM is derived based on current data (Figure 2). After synthesis in the cytoplasm, LPS flips across the IM by MsbA. At the periplasmic side of the IM, LPS most likely localizes to LptC that has been suggested to bind LPS. The energy required for LPS release from the IM may be provided by ATP hydrolysis of LptB that induces conformational changes in this protein. These conformational changes may then be passed on to LptF and/or LptG and finally to LptC that release LPS from the IM. The periplasm-spanning LptA is a likely candidate to accept LPS from LptC and facilitate transport across the periplasm forming a bridge between the IM and OM components of the Lpt system. After crossing the periplasm, LPS incorporate into the OM with the help of LptDE complex. The LPS transport system includes a lot of potential targets on Gram-negative bacteria especially LptDE complex.
Figure 2. Model for the LPS transport system Lpt. (Santambrogio et.al. 2013)
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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