Scientists from the University of Leeds say they have identified a key process in the way bacteria protect themselves from attack and that their finding heralds a potential new strategy in the hunt for antibiotics.

The researchers pieced together how bacteria build their outer, defensive wall. The team focused on the gram-negative bacteria E. coli, but the process they have discovered is shared by many pathogenic gram-negative bacteria so it could have importance for tackling other gram-negative pathogens, including the top three on the World Health Organization’s list of priority pathogens.

The study “Inter-domain dynamics in the chaperone SurA and multi-site binding to its outer membrane protein clients” appears in Nature Communications.

“The periplasmic chaperone SurA plays a key role in outer membrane protein (OMP) biogenesis. E. coli SurA comprises a core domain and two peptidylprolyl isomerase domains (P1 and P2), but its mechanisms of client binding and chaperone function have remained unclear. Here, we use chemical cross-linking, hydrogen-deuterium exchange mass spectrometry, single-molecule FRET and molecular dynamics simulations to map the client binding site(s) on SurA and interrogate the role of conformational dynamics in OMP recognition,” write the investigators.

“We demonstrate that SurA samples an array of conformations in solution in which P2 primarily lies closer to the core/P1 domains than suggested in the SurA crystal structure. OMP binding sites are located primarily in the core domain, and OMP binding results in conformational changes between the core/P1 domains.”

“Together, the results suggest that unfolded OMP substrates bind in a cradle formed between the SurA domains, with structural flexibility between domains assisting OMP recognition, binding and release.”

Antonio Calabrese, PhD, University Academic Fellow in the Astbury Centre for Structural Molecular Biology, led the research.

“Our findings are changing the way we think about the way these cells constantly renew and replenish the proteins that make up the outer membrane,” he said. “Understanding that process of how bacteria build their cell wall in greater detail may identify ways we could intervene and disrupt it. In doing so, we can either destroy the bacteria altogether or reduce the rate at which they divide and grow, making bacterial infections less severe.”

Calabrese added that the research is just beginning but that it could result in new, drug-based therapies that work either alone or with existing antibiotics to target disease-causing bacteria.

The research has focused on the role of a protein called SurA. Known as a chaperone, the job of SurA is to martial other proteins from where they are made, at the center of the cell, to where they are needed, in this case to bolster the bacterium’s outer wall.

Without the chaperone SurA, the essential proteins needed to build the cell wall run the risk of losing their structural integrity on their journey to the outer membrane. Using advanced analytical techniques, the scientists mapped how the chaperone SurA recognizes proteins to transport them to the bacterial outer membrane.

According to Calabrese, “For the first time we have been able to see the mechanism by which the chaperone, SurA, helps to transport proteins to the bacterial outer membrane. In effect it does this by cradling the proteins, to ensure their safe passage. Without SurA, the delivery pipeline is broken, and the wall cannot be built correctly.”

“This is an exciting discovery in our quest to find weak spots in a bacteria’s armory that we can target to stop bacterial growth in its tracks and build much-needed new antibiotics,” noted Sheena Radford, PhD, Director of the Astbury Centre for Structural Molecular Biology. “It’s early days, but we now know how SurA works and how it binds its protein clients. The next step will be to develop molecules that interrupt this process, which can be used to destroy pathogenic bacteria.”

Previous articleIndia’s Center of Innovative and Applied Bioprocessing to Work on Bioproduction of Potential COVID-19 Therapies
Next articleSARS-CoV-2 Infection of Gut Organoids Bolsters Case for Intestinal Transmission