Researchers at the University of East Anglia say they have found an Achilles' heel in the defensive barrier that surrounds drug-resistant bacterial cells. They believe their findings could open the door to new drugs that kill such “superbugs” by bringing down their defensive walls rather than attacking the bacteria itself. The team published its study (“Structural basis for outer membrane lipopolysaccharide insertion”) in Nature.
The World Health Organization has warned that antibiotic-resistance in bacteria is spreading globally, causing severe consequences. And even common infections that have been treatable for decades can once again kill.
The university researchers investigated gram-negative bacteria, which are particularly resistant to antibiotics because of its cells’ impermeable lipid-based outer membrane. This outer membrane prevents attacks from the human immune system and antibiotic drugs. Although the barrier allows the pathogenic bacteria to survive, removing it causes the bacteria to become more vulnerable and die.
Until now little has been known about exactly how the defensive barrier is built. The new findings reveal how bacterial cells transport the barrier building blocks (lipopolysaccharides) to the outer surface.
“We report the first crystal structure of the unique integral membrane LPS translocon LptD–LptE complex. LptD forms a novel 26-stranded β-barrel, which is to our knowledge the largest β-barrel reported so far,” wrote the investigators. “LptE adopts a roll-like structure located inside the barrel of LptD to form an unprecedented two-protein ‘barrel and plug’ architecture. The structure, molecular dynamics simulations, and functional assays suggest that the hydrophilic O-antigen and the core oligosaccharide of the LPS may pass through the barrel, and the lipid A of the LPS may be inserted into the outer leaflet of the outer membrane through a lateral opening between strands β1 and β26 of LptD. These findings not only help us to understand important aspects of bacterial outer membrane biogenesis, but also have significant potential for the development of novel drugs against multi-drug resistant pathogenic bacteria.”
“We have identified the path and gate used by the bacteria to transport the barrier building blocks to the outer surface,” explained Prof. Changjiang Dong, from UEA’s Norwich Medical School. “Importantly, we have demonstrated that the bacteria would die if the gate is locked.”
“The really exciting thing about this research is that new drugs will specifically target the protective barrier around the bacteria, rather than the bacteria itself,” added Haohao Dong, Ph.D., lead author on the paper. “Because new drugs will not need to enter the bacteria itself, we hope that the bacteria will not be able to develop drug resistance in the future.”