Mechanism Behind Drug-Resistant Bacteria Discovered

Information about the beta-barrel assembly machinery complex could lead to new treatments for drug-resistant bacteria.

Investigators in a recent study discovered new ways in which bacteria build up their defenses and become drug-resistant.

This new understanding could potentially assist scientists in creating new treatments for resistant bacteria, a phenomenon that has become an increasingly large problem in the United States. Many powerful antibiotics for conditions such as whooping cough or salmonella have been losing their efficacy due to resistance.

Other researchers have found that a pond virus and combinations of antibiotics could help combat drug-resistant strains, but little is known about the mechanisms behind the resistance itself. With increased knowledge, it is likely that more treatment options will be created.

The investigators in the current study, published by Nature Communications, discovered novel information about how the protein complex beta-barrel assembly machinery (BAM) operates. The BAM complex helps inserts other bacterial proteins in the bacteria’s in the protective outer layer.

This protective layer is needed for the bacteria to survive and spread.

The BAM complex sits in the outer membrane of Gram-negative bacteria, and inserts myriad proteins in the outer membrane to protect against antibiotic attacks, according to the study.

“This is a complex molecular machine involved in keeping bacteria alive, and we know that mutations in it are lethal to the bacteria. Some beautiful work by other labs has shown that BAM exists in 2 different shapes -- an open and closed form -- but the open form seemed to require part of the complex to fall apart,” said researcher Neil Ranson, BSc, PhD. “Our work shows for the first time the intact BAM complex in this open state. Now we have been able to see the intact structure in this way, it gives us new clues about how BAM works and about how to develop ways to stop it functioning.”

Previously, investigators used X-ray crystallography to show the barrel-shaped BAM complex could be both open and closed. It is generally thought that the change in shape is essential for proteins to enter the membrane.

The current investigators used advanced electron microscopes to view the structure of BAM in an open state through freezing the complex. Previous imaging of the structures lacked 1 of the 5 proteins that comprise the complex, called BamB.

The novel images of the BAM complex show that the BAM barrel can open with BamB there. This new insight will be helpful in developing new ways to kill resistant bacteria, and investigators believe that these changes are potentially how BAM works, according to the study.

“If BAM cannot do its job, bacteria won't survive and they would be prevented from spreading diseases,” said researcher Sheena Radford, BSc, PhD. “The challenge, now we understand more about how BAM works, is for the scientific community to develop drugs which can target it and replenish our shrinking arsenal of antibiotics to treat bacterial infections.”