Study Yields New Target to Fight Antibiotic Resistance
The Gram-negative bacterial outer membrane (OM) is a unique bilayer that forms an efficient permeation barrier to protect the cell from noxious compounds.
The defining characteristic of the OM is lipid asymmetry, with phospholipids comprising the inner leaflet and lipopolysaccharides comprising the outer leaflet. This asymmetry is maintained by the Mla pathway, a six-component system that is widespread in Gram-negative bacteria and is thought to mediate retrograde transport of misplaced phospholipids from the outer leaflet of the OM to the cytoplasmic membrane.
Now, scientists at the Newcastle University have identified a protein that acts as a “membrane vacuum cleaner” — an attribute that means it could serve as a new target for antibiotics.
The asymmetry and permeability barrier of the outer membrane of a bacteria must be restored in order to keep the bacterium healthy, which means those phospholipid molecules must be removed. This is the job of the maintenance of lipid asymmetry (Mla) system, which most Gram-negative bacteria have. The focus of the recent research is the MlaA protein, a component of the Mla system.
The team, through the investigation, reveal how the removal of certain lipids from the outer membrane may provide
a vulnerability for gram-negative bacteria. They propose that this system could be exploited by drugs to decrease bacterial virulence and to make various antibiotics more effective.Newcastle University Professor of Membrane Protein Structural Biology and lead author Bert van den Berg explained in a press release: “Our three-dimensional structures and functional data show that MlaA forms a donut in the inner leaflet of the outer membrane. This binds phospholipids from the outer leaflet and removes these via the central channel, somewhat similar to a vacuum cleaner.”
“Our study illuminates a fundamental and important process in Gram-negative bacteria and is a starting point to determine whether the Mla system of Gram-negative pathogens could be targeted by drugs to decrease bacterial virulence, and to make various antibiotics more effective.” Concludes Bert.
