Antibiotic-resistant superbugs may be overcome by ‘breaking down their walls’

Posted on Posted in Antibiotics, Bacteria, Medical News, Pharmaceuticals

A new study that uncovers a mechanism that allows bacteria to fend off immune cells and drugs could pave the way for a new generation of drugs that kill the microbes by bringing down their cell walls. The finding offers a new direction to pursue in the fight against antibiotic-resistant superbugs.

e-coli-bacteria

The researchers examined the structure of the beta-barrel assembly machinery in the cell wall of the Gram-negative bacterium Escherichia coli.

In his Nobel Prize acceptance speech in 1945, Sir Alexander Fleming – the man who discovered penicillin and ushered in a new era of medicine – predicted that the day would come when, through injudicious use, antibiotics would lose their power to kill bacteria.

Now, some 7 decades later, the prediction has come to pass – infection-causing bacteria are becoming resistant faster than we can develop new drugs to fight them.

In 2014, the World Health Organization (WHO) declared antimicrobial resistance to be an “increasingly serious threat to global public health” that requires action across all sectors of government and society.

Recently, Medical News Today has reported on a number of studies that offer a glimmer of hope. For example, one approach scientists at Northeastern University in Boston, MA, are pursuing is the idea ofsynthetic immune cells to boost infection-fighting capacity in people with weakened immune systems.

The new study, from the University of East Anglia (UEA) in the UK and published in the journal Nature, examines the nature of the drug-resistant bacteria themselves and reveals the mechanism by which they are able to defend against onslaught by antibiotic drugs.

Lead investigator Changjiang Dong, a professor in UEA’s Norwich Medical School, says:

“Many current antibiotics are becoming useless, causing hundreds of thousands of deaths each year.”

The researchers suggest their findings will not only pave the way for a new generation of drugs that kill superbugs by bringing down their defensive walls, but will also increase our understanding of what can go wrong in human cells indiabetes and brain-wasting disorders like Parkinson’s disease.

Impermeable outer cell membrane

For their study, the team focused on a group of microbes known as Gram-negative bacteria, because, as Prof. Dong explains:

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

A distinctive feature of Gram-negative bacteria is their impermeable outer cell membrane that acts as a defensive barrier against attack by the immune system and drugs. But if the barrier is removed, the bacteria become more vulnerable and are easier to kill.

In previous work, Prof. Dong and colleagues had found the “Achilles heel” in the membrane. In the new study, the team probed further and discovered the mechanism – the assembly machinery – that builds and maintains the barrier.

The barrier contains proteins that form the gates of the cell wall. These proteins – called beta-barrel proteins – control the entry of nutrients and the exit of important molecules that the cells secrete. Prof. Dong says:

“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 team used Diamond Light Source – one of the world’s most advanced scientific machines that produces light 10 billion times brighter than the sun – to examine the structure of the barrier in atomic detail.

Beta-barrel assembly machinery assembles in two states

The team focused on the structure of the barrier in the Gram-negative bacteria Escherichia coli, whose beta-barrel assembly machinery comprises five subunits: BamA, BamB, BamC, BamD and BamE.

The researchers wanted to find out exactly how these BAM subunits work together to insert proteins into the defensive outer wall of the E. coli cell.

They found that the structure assembles in two states – a starting state and a finishing state, as Prof. Dong explains:

“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.”

Prof. Dong says their study is the first to show the entire BAM complex and paves the way for developing a new class of drugs that target the BAM in the outer membrane of Gram-negative bacteria, which is essential for their survival.

There is a similar complex in human cells, called the sorting and assembly machinery complex (SAM), that builds the outer membrane proteins of mitochondria – the tiny units that provide cells with energy. Prof. Dong suggests:

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

Credit: Catharine Paddock PhD, http://www.medicalnewstoday.com/

Picture Credits: www.shutterstock.com &  www.foundwalls.com

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