The fight against antibiotic-resistant superbugs has only just begun, but research published Monday in the journal Nature suggests there may be hope. The new findings give us insight into how we might win bacterial wars by busting up some walls, so to speak -- hijacking a system that many bacterial cells use to maintain a defensive barrier against external threats, be they pharmacological or immunological.
Researchers from the University of East Anglia are the first to describe a novel method by which proteins are stuck into the outer membrane of the Gram-negative bacteria E. coli. This is important because it’s critical that we find new ways to bring down harmful Gram-negative bacteria, which can cause cholera, plague, pneumonia and infections of the bloodstream, surgical sites and wounds, as well as meningitis -- and which happen to be gosh darned hard to kill. Gram-negative bacteria are notorious for their drug resistance and ability to wreak havoc in health-care settings.
The secret behind their relative hardiness lies in the bacterial outer membrane investigated in the new paper. A hallmark of the Gram-negatives, the presence of this membrane makes the bacteria less likely to succumb to treatment.
All bacteria have what I’ll refer to here as an “inner membrane,” a kind of cellular envelope that keeps all the bacterium’s junk in a neat little blob. But Gram-negative bacteria have a second layer -- an outer membrane. The lack of this outer membrane makes Gram-positive bacteria more susceptible to antibiotics; the presence of it makes Gram-negative bacteria tough as nails.
Gram-negative bacteria each have an inner membrane, a thin layer or goo called periplasm, and an outer membrane. The outer membrane is studded with proteins that do fundamental biological processes, working as a doorman for important tasks like nutrient transport, sending out and receiving proteins, and secretion.
The bacteria need to be able to make, transport and correctly insert helpful, complicated blobs known as outer membrane proteins, or OMPs, into the outer membrane. OMPs handle the transactions between the inside and outside of the membrane, serving as a kind of liaison between the outside world and the cosy inner workings of Escherichia coli.
Researchers at UEA have discovered the mechanism by which E. coli puts the OMPs into its precious outer membrane. And if you know how a cell is doing something, well, it becomes quite a bit easier to dream up ways to stop that process.
Here’s how it works, according to the new study: The outer membrane proteins are made in the soupy inside of the cell and are then transported across the inner membrane to that thin goo layer between the inner and outer membrane, the periplasm. From here, it falls to the beta-barrel assembly machinery, known as BAM, to correctly assemble and insert the OMPs into the cell wall. The BAM complex is tasked with making the gates to inside the cell -- gates that, when functioning properly, keep the cell safe from outside attack. The individual structures of the BAM complex have been described, but until now we didn’t know the mechanism of their action or what the complete structure of the complex looks like.
In the paper released Monday, the researchers describe two unique states of the BAM architecture, an inward-open state and a novel lateral-open state. By doing an interesting rotation-and-tilt motion, the ring-like subunits of the BAM complex work to fold and properly insert OMPs into that all-important outer membrane. The researchers hypothesize that the two structures observed represent the resting state of the complex, as well as its post-insertion state.
This finding is particularly exciting because it opens up a new way to fight hard-to-kill Gram-negative bacteria. But what would these new drugs do?
According to the group leader, Changjiang Dong from UEA, “Our work and others suggested that the [drugs] would kill E. coli if the small compounds could disrupt the interaction between the subunits BamA and BamD,” two of the subunits that have been identified as critical to the BAM complex and thus critical for cell survival.
“The bacteria would die if the compounds are located into the BamA of the BAM complex and prevent the lateral opening or the movements of the first six strands of the barrel," he said. The strands of the barrel are required for functionality in this complex; stopping them could halt the action of BAM, crippling the cell.
With knowledge of this mechanism, researchers can now begin to figure out how to use medicine to disrupt it.
“We will start to design small molecules and test whether the design molecules can kill bacteria, in particular drug-resistant Gram-negative bacteria," he said.
One subunit, BamA, is able to be reached from the outside of the cell, making it a promising target with which to begin the search. “The drugs could direct target the BamA from the other side of the bacteria,” Dong explained.
Notably, the power plants of human cells, called mitochondria, also have an outer membrane; dysfunction in this membrane has been linked to diabetes, Parkinson's disease and other neurodegenerative diseases, making the new findings particularly salient for those areas of research.
And the best part? This research was conducted in part with Diamond Light Source, a piece of ultra-advanced scientific equipment that is capable of producing light 10 billion times brighter than that of our sun, allowing scientists to examine almost any material in atomic detail.
The race against drug resistance might be in its infancy but, as promising research like this so keenly demonstrates, there is a bright glimmer of hope on that horizon.
Leigh Cowart is a freelance journalist covering science, sex, and sports. She is fully vaccinated for rabies.