Options for treating Gram-negative bacterial infections are limited and current therapies are progressively less effective due to the rapid development of multi-drug resistance in the clinic. This necessitates a renewed focus on the development of novel antibacterials directed at these pathogens. However, drug discovery against Gram-negatives is a challenge because their outer membrane and active efflux conspire to prevent or reduce the access of inhibitor molecules to the intracellular space where the targets are located. This characteristic protective impermeability of the outer membrane is largely determined by lipopolysaccharide (LPS), the major component of the outer leaflet of the outer membrane. Perturbation or truncation of LPS can render the cells susceptible to several currently used drugs or investigational compounds that are usually inactive against Gram-negatives. In addition, LPS biosynthesis and its transport to the outer membrane are essential for the growth of many gram-negative bacteria. Therefore, disruption of LPS biosynthesis or assembly is a promising antibacterial pathway target and recent reports have described investigational LpxC (biosynthesis) and LptD (transport) inhibitors. Despite this interest and significant recent progress in delineating details of LPS biosynthesis/assembly, cellular and molecular mechanisms of LPS function in drug resistance and bacterial proliferation remain elusive. We employ a range of genetic, molecular biological, and microscopic techniques to better understand LPS functional roles in bacterial cells with a view to enabling novel antibacterial development or treatment strategies.
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