The study, which was undertaken by researchers at Kanazawa University and the Japan Agency for Medical Research and Development, expands upon research which began in 1982 that reported a link between chronic gastritis and stomach bacterium Helicobacter pylori, triggering a flurry of research into this newly-identified pathogen.

These studies made it clear that in addition to its involvement in gastritis, H. pylori was a significant factor in the development of both peptic ulcers and gastric cancer. But while the link between the bacterium and disease was clear-cut, exactly how H. pylori caused gastric tumours remained the subject of much debate.

Now, four decades later, the link has finally been explained. 

“We previously showed that tumour necrosis factor alpha (TNF-α), a cytokine that causes inflammation, promotes gastric tumour formation by activating a protein called NOXO1,” said lead author of the study Dr Kanae Echizen. “What we didn’t know was exactly how NOXO1 induces tumour formation in the stomach.”

NOXO1 is a component of the NOX1 complex, which produces tissue-damaging molecules called reactive oxygen species (ROS). This can result in mutations in the DNA of stomach cells, leading to tumour formation. Inflammation caused by H. pylori infection also produces ROS, increasing oxidative stress in the stomach.

The researchers showed that inflammation caused excess production of NOX1-complex proteins in response to signals from NF-κB, a regulatory protein that turns on genes to combat stress or bacterial infection, and which is a major player in the inflammatory response. They also found that NOX1/ROS signalling caused gastric epithelial stem cells to multiply uncontrollably, resulting in tumour formation.

Knowing this, the researchers used a drug to suppress the activity of the NOX1 complex, which halted the growth of gastric cancer cells. Even more excitingly, disruption of NOXO1 in a mouse gastritis model stopped the proliferation of epithelial stem cells.

“We have finally been able to show that inflammation enhances the expression of NOXO1, which induces the proliferation of gastric epithelial stem cells, leading to gastric tumours,” Dr Masanobu Oshima, senior author of the study explained. “Gastric cancer is the fourth most common cancer worldwide and has the second highest mortality rate. If we can disrupt the NOX1/ROS signaling pathway in situ, we may be able to prevent the development of this aggressive disease.”

For further details of the study click here. 

bacteria

Researchers have uncovered the unique method a certain bacteria uses to deliver toxins.

Scientists at Binghampton University, State University of New York, uncovered how the gram-negative bacterium communicates through transporting small molecules. The understanding of these mechanisms could help to design better methods of controlling and blocking these toxins.

Assistant Professor Xin Yong and graduate student Ao Li from the Department of Mechanical Engineering, along with Associate Professor Jeffrey W. Schertzer from the Department of Biological Sciences worked on the study.

The research team mentioned how the communication molecules stimulate the production of outer membrane vesicles, and how these ‘packages’ that contain highly concentrated toxins, bud off from the surface of the bacterium. The researchers wanted to work on a model to understand more about how the communication molecule inserts itself into the membrane of bacteria to physically stimulate the production of the toxin delivery vesicles. 

“It’s hard to see the molecular detail at that level,” explained Prof Schertzer. “But with Dr Yong’s expertise, we were able to build a computational model that helped us understand what actually goes on between individual molecules.”

The model allowed the team to identify details of the molecule, and understand its reaction with the membrane.

“Our most important finding is that the communication molecule needs to enter the membrane in a very specific way,” said Prof Schertzer. “It folds itself like a book, then will expand once it has entered the membrane.”

“Gram-negative bacteria likely all have similar types of communication molecules. We focused on the PQS [Pseudomonas Quinolone Signal] molecule of Pseudomonas aeruginosa because it was the first discovered and is the best studied,” said Dr Yong. “Other Gram-negative species, such as E. coli, may be transferring their own communication molecules in a similar way.”

“This study was a testament to how beneficial interdisciplinary work can be,” said Prof Schertzer. “We had reached a limit with what could be done experimentally and needed Dr Yong’s model to develop a rationale for how the molecule was interacting with the membrane. Most importantly, this work has generated a wealth of new questions that we are now continuing to investigate.”

The study was published in the Journal of Biological Chemistry.

antibiotic

Scientists have identified how an enzyme is able to create potent antibiotics.

Researchers at Rutgers University, and universities in Russia, Poland and England studies an enzyme called McbBCD. This protein makes microcin B17 from a smaller protein known as a peptide.

The bacterial toxin microcin B17 is able to inhibit DNA replication in many enteric bacteria, which leads to huge DNA degeneration and ultimately cell apoptosis (cell death). 

This natural, potent antibiotic, microcin B17 is able to kill harmful E. coli bacteria. Since resistance to antibiotics (because of their misuse, and overuse) is a huge threat to humanity, scientists are keen to quickly develop new drugs. Naturally occurring antibiotics, such as microcin B17, have generally evolved over years and could be a good option to help overcome current resistance. 

The team investigated McbBCD, an enzyme that makes the naturally occurring antibiotic, microcin B17 from a peptide. Despite knowing about microcin B17 for a while, and about its unusual chemical structure, scientists still did not understand the molecular ‘machinery’ that made the compound until recently.

Principle Investigator at the Waksman Institute of Microbiology and senior author of the study, Professor Konstantin Severinov writes how, along with his team, he discovered the enzyme that triggered two chemical reactions that produce several chemical ‘cycles’ that are required for antibacterial activity. Dr Severinov is also a Professor of Molecular Biology and Biochemistry at  Rutgers University-New Brunswick.

“Our research allows rational design of new peptide compounds that could become treatments ranging from antimicrobials to anticancer drugs,” Prof Severinov said.

“There may be a trove of new antibiotics that could be made from peptides, using enzyme machines like McbBCD as a production tool.”

The team collaborated with researchers from the Russian Academy of Sciences, Skolkovo Institute of Science and Technology (Russia), Jagiellonian University (Poland) and the John Innes Centre (England).

The researchers published the results of the study in the journal Molecular Cell.

antibiotics

Biomedical engineers at Duke University have shown experimentally that there is more than one flavour of antibiotic resistance and that it could – and should – be taken advantage of to keep first-line antibiotics in our medical arsenal.

In the study, the researchers showed why doctors should be paying more attention to whether a pathogen is resistant or merely resilient against common beta-lactam antibiotics, such as penicillin and its derivatives.

Resistant strains of bacteria can soldier through a dose of beta-lactam antibiotics with little disturbance to their population levels. Resilient strains, however, suffer a population crash before their community can secrete enough beta-lactamase enzymes to degrade the antibiotic to a tolerable level. If clinicians test an infection by dosing a culture and checking only the end results, they miss the difference between resistant and resilient responses.

“Clinicians have not historically distinguished between these two scenarios,” said Dr Lingchong You, the Paul Ruffin Scarborough Associate Professor of Engineering at Duke. “But as beta-lactam-tolerant pathogens become more common, I believe this distinction could become extremely important.”

While an individual bacterium can be resistant to antibiotics, resilience only arises within a community. This happens when bacterial cells produce enough beta-lactamases to degrade the antibiotics, but not enough to save themselves from the initial onslaught. As some cells die and release more and more of the enzyme, however, the population as a whole eventually rids their environment of the antibiotic.

In the study, Prof You and Dr Hannah Meredith, now a postdoctoral researcher at the London School of Hygiene and Tropical Medicine, tracked the populations of several beta-lactam-tolerant strains of bacteria over time when exposed to beta-lactam antibiotics. They then used the responses to quantify the bacteria population’s levels of resistance and/or resilience, creating a method to put values to resistance or resilience for the first time.

In practice, the study offers a framework for researchers to begin designing tests that can swiftly measure an infection for these two separate responses. In You’s opinion, it’s a procedure that will have to become more common in the future.

With a measure of a strain’s resilience in hand, doctors could prescribe a regimen of antibiotics perfectly timed to hit an infection repeatedly during the colony’s weakest points. This approach could allow doctors to continue using first-line antibiotics on pathogens that otherwise would be characterized as resistant and treated with more powerful antibiotics, a practice that will degrade the medicine’s usefulness over time.

“We’re still in a stage where doctors don’t do a detailed diagnosis of what specific infection a patient is suffering from, they just prescribe these antibiotics because they’ll probably work after two weeks. And if they don’t, they’ll just try a different one,” said You. “But I think as these beta-lactam-resistant strains continue to spread around the world and become more common, our diagnoses will have to catch up so we can provide more tailored dosing protocols.”

The study was published in the journal Science Advances.