UEA scientists pave the way for a new generation of superbug drugs
Scientists at the University of East Anglia are getting closer to solving the problem of antibiotic resistance
New research published in Nature reveals the mechanism by which drug-resistant bacterial cells maintain a defensive barrier. The findings pave the way for a new wave of drugs that kill superbugs by bringing down their defensive walls rather than attacking the bacteria, meaning that, in the future, bacteria may not develop drug-resistance at all.
Unravelling this mechanism could also help scientists to understand more about human cell dysfunctions linked to disorders such as diabetes, Parkinson’s and other neurodegenerative diseases.
The team, supported by the Wellcome Trust, used Diamond Light Source to investigate Gram-negative bacteria. Diamond produces intense light (10 billion times brighter than the sun), allowing scientists to explore almost any material in atomic detail.
Gram-negative bacteria are particularly resistant to antibiotics because of their impermeable lipid-based outer membrane. This outer membrane acts as a defensive barrier against attacks from the human immune system and antibiotic drugs. However, removing this barrier causes the bacteria to become more vulnerable and die.
The research team had previously found a so-called Achilles’ heel in this defensive barrier. But, until now, how this cell wall was built and maintained – the assembly machinery - was unknown. Lead researcher 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 antibiotics are becoming useless, causing hundreds of thousands of deaths each year.’
‘The number of superbugs is increasing at an unexpected rate and Gram-negative bacteria are some of the most difficult ones to control because they’re so resistant to antibiotics,' added Dong.
He continued: ‘All Gram-negative bacteria have a defensive cell wall. Beta-barrel proteins form gates in the cell wall to import nutrition and secrete important biological molecules. The beta-barrel assembly machinery (BAM) is responsible for building the gates (beta-barrel proteins) in the cell wall. Stopping the assembly machine from building the gates in the cell wall cause the bacteria to die.’
Scientists studied the Gram-negative bacteria, E. coli, in which the beta-barrel assembly machinery contains five sub-units (known as BamA, BamB, BamC, BamD and BamE). They wanted to know exactly how these sub-units work 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: starting and finishing. We found that the five sub-units 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 to the development of next-generation drugs.’
‘In human mitochondria, a similar complex called sorting and assembly machinery complex (SAM) is responsible for building the membrane proteins in the outer membrane of mitochondria. Dysfunctions in these proteins are linked to disorders such as diabetes, Parkinson’s and other neurodegenerative diseases, so we hope that this work will also help us to better understand these human conditions too,’ Dong concluded.