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Superbugs

We cannot escape the issue of antibiotic resistance which is becoming an increasing concern in today's society. 

UEA, however, has been undertaking ground-breaking research to help combat this increasingly worrying problem and transforming the ways in which we think about a solution.

Our research, which was published in Nature, found that drug resistant bacterial cells are able to maintain a defensive barrier. Without knowing this, we would not have known that we could destroy their defensive walls without attacking the bacteria too. This means that in the future, the bacteria may not actually become resistant to treatment, a huge advancement in knowledge. 

Not only has this progress in research helped us to gain a better understanding of how we could solve the problem of antibiotic resistance, the mechanism may also contribute to scientists’ understanding of human cell abnormalities linked with a range of disorders including diabetes, Parkinson’s and other neurodegenerative diseases. 
UEA’s research team used the Diamond Light Source, a scientific machine that is one of the most advanced in the world, to investigate a class of bacteria called ‘Gram-negative bacteria’. The outer-membrane of this bacteria is lipid-based and highly impermeable, meaning it is especially resistant to antibiotics. 

The outer-membrane of a cell plays an important role in its resistance to drugs. It acts as a defensive wall to stop attacks from the human immune system and antibiotic drugs whilst allowing the pathogenic bacteria to survive. Therefore, by removing the outer-membrane means the bacteria is more open to attack and consequently less likely to survive. 

Lead researchers Prof Changjiang Dong, from UEA’s Norwich Medical School said: 
“Bacterial multi-drug resistance, also known as antibiotic resistance, is a global health challenge. Many current antibiotics are becoming useless, causing hundreds of thousands of deaths each year. The number of super-bugs is increasing at an unexpected rate.”

“Gram-negative bacteria is one of the most difficult ones to control because it is so resistant to antibiotics.

“All Gram-negative bacteria have a defensive cell wall. Beta-barrel proteins form the gates of the cell wall for importing nutrition and secreting important biological molecules.  

“The beta-barrel assembly machinery (BAM) is responsible for building the gates (beta-barrel proteins) in the cell wall.  
“Stopping the beta-barrel assembly machine from building the gates in the cell wall cause the bacteria to die.”

The scientists looked at E.Coli, a gram-negative bacteria, in which the beta-barrel assembly machinery contains five subunits, called BamA, BamB, BamC, BamD, BamE. They wanted to know how the subunits worked together to insert the outer membrane proteins into the outer membrane or cell wall.  

Prof Dong said: “Our research shows the whole beta-barrel assembly machinery structures in two states - the starting and finishing states. We found that the five subunits form a ring structure and work together to perform outer membrane protein insertion using a novel rotation and insertion mechanism.

“Our work is the first to show the entire BAM complex. It paves the way for developing new-generation drugs.

“The beta-barrel assembly machinery is absolutely essential for Gram-negative bacteria to survive. The subunit BamA is located in the outer membrane and exposed to the outer side of the bacteria, which provides a great target for new drugs.
 “In Human mitochondria, a similar complex called sorting and assembly machinery complex (SAM) is responsible for building the outer membrane proteins in the outer membrane of mitochondria.

“Dysfunction of mitochondria outer membrane proteins are linked to disorders such as diabetes, Parkinsons and other neurodegenerative diseases, so we hope that this work may also help us to better understand these human diseases too.”

Picture

Prof Changjiang Dong

Professor of Molecular Medicine, Norwich Medical School

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