‘It paves the way for developing new-generation drugs’
A new generation of antibiotics could emerge from a study revealing the hidden Achilles’ heel of many drug-resistant superbugs, scientists said.
Powerful light beams many millions of times brighter than the Sun have for the first time taken detailed images of the complex, molecular structure that helps to build the protective cell wall of disease-causing bacteria.
Researchers believe that understanding how this molecular machinery is arranged at the atomic scale within the bacterial cell wall holds the key to developing new kinds of antibiotic drugs that can breach the outer defences of resistant microbes.
The study revealed how the structure, known as the beta-barrel assembly machinery (BAM), is made up of five protein subunits that work together to build the protein gateways of the bacterial cell wall, which allow vital nutrients to flow into the microbial cell.
The BAM machinery is found in all “gram-negative bacteria” – a class of microbes that causes a range of potentially lethal infections from pneumonia and meningitis to blood sepsis and food poisoning. Antibiotic resistance is a particular problem with gram-negative bacteria.
By mapping the three-dimensional positions of the five BAM subunits, scientists believe they have finally found a way of understanding how to block the machinery that builds the cell wall’s gateways, and in doing so starve the microbe of vital nutrients.
Scientists said the findings pave the way for a new generation of drugs that kill superbugs by tearing down their defensive walls rather than attacking the bacteria itself. This approach might even prevent the development of further drug-resistance, they added.
“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 superbugs is increasing at an unexpected rate,” said Professor Changjiang Dong of the University of East Anglia in Norwich, who led the study published in the journal Nature.
“Gram-negative bacteria are one of the most difficult ones to control because they are 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,” Professor Dong said.
“The beta-barrel assembly machinery (BAM) is responsible for building the gates – the 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,” he said.
Unravelling the BAM mechanism could also help to understand human cell dysfunctions linked to disorders such as diabetes, Parkinson’s and other neurodegenerative diseases, Professor Dong said, as similar molecular machinery is also found in the cell membranes of human mitochondria – the microcopic “power packs” of the cells.
“In human mitochondria, a similar complex called sorting and assembly machinery (SAM) is responsible for building the outer membrane proteins in the outer membrane of mitochondria,” he said.