Potentially exploitable weakness found in bacteria’s outer armor

For bacteria, the first line of defense is the cell wall, which keeps toxins such as antibiotics out. Now, researchers have discovered a key mechanism that bacteria use to build their cell walls, which could present a new target in the ongoing quest to develop new drugs.

The cell wall of bacteria functions kind of like an exoskeleton, giving them shape and structure and protecting them from outside incursion. Since this is vital for the organism’s survival, the cell wall is an attractive target for drug development, ever since the discovery of the original antibiotic, penicillin.

Now, researchers from the University of Leeds have closely studied just how bacteria build their cell walls – and discovered a new chink in this armor that could be exploited. The team focused on a protein called SurA, which chaperones other proteins from the center of the cell outwards to help build the cell wall.

The team used a range of advanced analytical techniques, including chemical cross-linking, mass spectrometry, and simulations to figure out just how SurA recognizes and ferries other proteins. The study was conducted in E. coli, but the team says that the same process is likely at work in many other gram-negative bacteria – a major category of pathogens.

“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,” says Antonio Calabrese, lead researcher on the study. “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.”

Understanding just how this crucial protein works may be the first step in finding ways to disrupt it. If SurA is inhibited, the team hopes, bacteria will struggle to build walls. This could kill them outright, make them much more vulnerable to existing drugs, or much less likely to grow and spread.

“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,” says Sheena Radford, an author of the study. “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.”

Similar studies in the past have attempted to get through the cell wall by disrupting other vital proteins like RodA, physically piercing them with metal nanoparticles, or even drilling through them with specialized molecules.

The new study was published in the journal Nature Communications.

Source: University of Leeds

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