New strategy to reduce antibiotic resistance using an extracellular polymeric substance inhibitor

Researchers from KU Leuven in Belgium have developed a new antibacterial strategy that weakens bacteria by preventing them from cooperating. The researchers showed that blocking slime (extracellular polymeric substance) production of salmonella bacteria weakens the bacterial community, making it easier to remove.

They used a chemical, antibacterial substance 2-cyclopentenyl-5-(4-chlorophenyl)-2-aminoimidazole, a specific member of the class of 5-aryl-2-aminoimidazoles as extracellular polymeric substance (EPS) inhibitor. Researchers at KU Leuven previously reported utility of 5-aryl-2-aminoimidazoles in preventing EPS production of salmonella bacteria.

The findings of this study are published in Nature Communications.

Traditional antibiotics kill or reduce the activity of individual bacteria. Some bacteria become resistant to these antibiotics, allowing them to grow further and take over from non-resistant ones. The use of antibiotics, therefore, causes more and more bacteria to become resistant to antibiotics. Bacteria, however, also exhibit group behavior: for example, they can make a protective slime layer or biofilm that envelops their entire bacterial community. The social behavior of bacteria is an interesting new target for antibacterial therapy. Their experiments also suggested a reduction of antibiotic resistance development.

Researchers note that there are several applications possible in agriculture, industry, and even households. To this end, the researchers collaborate with experts in various applications, and with producers of animal feeds and cleaning products and disinfectants. The researchers are also investigating whether they can reproduce the phenomenon in other forms of microbial collaboration, and with other bacteria.

Antibiotics versus surgery in acute appendicitis

A systemic review of research literature by scientists at the University of Southampton shows that antibiotics may be an effective treatment for acute non-complicated appendicitis in children, instead of surgery. The research paper is published in Pediatrics.

The condition, which causes the appendix – a small organ attached to the large intestine – to become inflamed due to a blockage or infection, affects mainly children and teenagers. Appendicitis is currently treated through an operation to remove the appendix, known as an appendicectomy, and it is the most common cause of emergency surgery in children.

The review, led by Nigel Hall, Associate Professor of Pediatric Surgery at the University of Southampton, assessed existing literature published over the past 10 years that included 10 studies reporting on 413 children who received non-operative treatment rather than an appendectomy. It shows that no study reported any safety concern or specific adverse events related to non-surgical treatment, although the rate of recurrent appendicitis was 14 per cent.

The review says that longer term clinical outcomes and cost effectiveness of antibiotics compared to appendicectomy require further evaluation, preferably as large randomized trials to reliably inform decision making.

To further this research Mr. Hall and his team in Southampton, along with colleagues at St George’s Hospital in Tooting, Alder Hey Children’s Hospital in Liverpool and Great Ormond Street Hospital, are currently carrying out a year-long feasibility trial which will see children with appendicitis randomly allocated to have either surgery or antibiotic treatment.

Reference: Georgiou, Roxani, Simon Eaton, Michael P. Stanton, Agostino Pierro, and Nigel J. Hall. “Efficacy and Safety of Nonoperative Treatment for Acute Appendicitis: A Meta-analysis.” Pediatrics, 2017.
doi:10.1542/peds.2016-3003.
Research funding: National Institute for Health Research Health Technology Assessment Programme (UK).
Adapted from press release by University of Southampton.

Research shows reduced Surgical Site Infections with use of Antimicrobial Sutures

New analyses of the published clinical studies indicate that antimicrobial sutures are effective for preventing surgical site infections (SSIs), and they can result in significant cost savings. The results are published in the British Journal of Surgery.

In one analysis that included 21 randomized clinical trials, investigators found a risk of 138 surgical site infections per 1000 procedures, and the use of sutures coated with the antimicrobial triclosan reduced this by 39. Investigators noted that sufficient evidence exists for a 15 percent relative risk reduction in SSIs when triclosan-coated sutures are used.

In an economic analysis of results from 34 studies, triclosan sutures were linked with an average cost savings per surgical procedure of  91.25 pounds across all wound classes when compared with non-antimicrobial-coated sutures.

“Antimicrobial sutures ought to be included into SSI care bundles and provide a further significant saving to National Health Service (England) surgical practice,” said Prof. David Leaper, lead author of the economic analysis.

Citations:

S. W. de Jonge, J. J. Atema, J. S. Solomkin and M. A. Boermeester. Meta-analysis and trial sequential analysis of triclosan-coated sutures for the prevention of surgical-site infection. British Journal of Surgery.
DOI: 10.1002/bjs.10445

D. J. Leaper, C. E. Edmiston Jr and C. E. Holy. Meta-analysis of the potential economic impact following introduction of absorbable antimicrobial sutures. British Journal of Surgery.
DOI: 10.1002/bjs.10443

Adapted from press release by Wiley publications.

Research unveils structure of crucial bacterial cell wall protein

Duke University researchers have provided the first close-up glimpse of a protein, called MurJ, which is crucial for building the bacterial cell wall and protecting it from outside attack. The research is published in Nature Structural and Molecular Biology.

Researchers at Duke University solved the structure of an enzyme that is crucial for helping bacteria build their cell walls. The molecule, called MurJ (shown in green), must flip cell wall precursors (purple) across the bacteria’s cell membrane before these molecules can be linked together to form the cell wall. This new structure could be important to help develop new broad-spectrum antibiotics. Credit: Alvin Kuk, Duke University

“Until now, MurJ’s mechanisms have been somewhat of a ‘black box’ in the bacterial cell wall synthesis because of technical difficulties studying the protein,” said senior author Seok-Yong Lee, Ph.D., associate professor of biochemistry at Duke University School of Medicine. “Our study could provide insight into the development of broad spectrum antibiotics, because nearly every type of bacteria needs this protein’s action.”

A bacterium’s cell wall is composed of a rigid mesh-like material called peptidoglycan. Molecules to make peptidoglycan are manufactured inside the cell and then need to be transported across the cell membrane to build the outer wall.

In 2014, another group of scientists had discovered that MurJ is the transporter protein located in the cell membrane that is responsible for flipping these wall building blocks across the membrane. Without MurJ, peptidoglycan precursors build up inside the cell and the bacterium falls apart. Many groups have attempted to solve MurJ’s structure without success, partly because membrane proteins are notoriously difficult to work with.

In this study, Lee’s team was able to crystallize MurJ and determine its molecular structure to 2-angstrom resolution by an established method called X-ray crystallography, which is difficult to achieve in a membrane protein. The structure, combined with follow-up experiments in which the scientists mutated specific residues of MurJ, allowed them to propose a model for how it flips peptidoglycan precursors across the membrane.

After determining the first structure of MurJ, Lee’s team is now working to capture MurJ in action, possibly by crystallizing the protein while it is bound to a peptidoglycan precursor. “Getting the structure of MurJ linked to its substrate will be key. It will really help us understand how this transporter works and how to develop an inhibitor targeting this transporter,” Lee said.

Lee’s group is continuing structure and function studies of other key players in bacterial cell wall biosynthesis as well. Last year, they published the structure of another important enzyme, MraY, bound to the antibacterial muraymycin.

Citation: Kuk, Alvin CY, Ellene H. Mashalidis, and Seok-Yong Lee. “Crystal structure of the MOP flippase MurJ in an inward-facing conformation.” Nature Structural & Molecular Biology (2016).
DOI: 10.1038/nsmb.3346
Research funding: Duke University
Adapted from press release by the Duke University.

New electrochemical biosensor system that can be used for point-of-care antibiotic testing could usher personalized antibiotic treatment

A team of researchers from the University of Freiburg has developed a system inspired by biology that can detect several different antibiotics in human blood or other fluids at the same time. This biosensor system could be used for medical diagnostics in the future, especially for point-of-care testing in doctors’ practices, on house calls and in pharmacies, as well as in environmental and food safety testing. The researchers focused their study on the antibiotics tetracycline and streptogramin in human blood.

The electrochemical biosensor system for point-of-care testing.
Photo: Andreas Weltin 

The researchers have recently published their results in Analytical Chemistry. Based on these findings, the group is currently working on developing a method to determine how quickly the human body breaks down antibiotics, thus enabling the dosage of medications to be adjusted to each patient. “This technology could pave the way for personalized antibiotic treatments in the future,” said the microsystems engineer Dr. Can Dincer, who is the head of the research team.

The all-too-frequent use of antibiotics in human and veterinary medicine causes pathogens to develop resistance. Multidrug resistant bacteria are the reason for an increasing number of life-threatening infections that are difficult to treat with medications available today. In this context, biosensors have so much potential in research, since they are inexpensive and easy to work with. It is expected that biosensors can be employed to customize antibiotic treatments to fit each patient`s requirements, thereby decreasing the development of resistant bacteria in the future.

The electrochemical biosensor platform was developed by Prof. Dr. Gerald Urban’s research group. It works with extremely small amounts of liquid. “The major advantage of this system is that we can measure up to eight different substances at the same time, quickly and simply,” Dincer said. The researchers combined their chip technology with a method developed earlier by the bioengineering expert Prof. Dr. Wilfried Weber, also from the University of Freiburg. The method is based on a naturally occurring sensor protein in resistant bacteria to recognize antibiotics and activate their defence mechanisms. These bacterial sensors react quickly, sensitively and specifically to antibiotics, which makes them ideal for analytical testing. Essentially, the bacteria are providing the researchers with a tool that can be applied to fight them back in the long-run.

Citation: Kling, André, Claire Chatelle, Lucas Armbrecht, Edvina Qelibari, Jochen Kieninger, Can Dincer, Wilfried Weber, and Gerald Urban. “Multianalyte Antibiotic Detection on an Electrochemical Microfluidic Platform.” Analytical Chemistry 88, no. 20 (2016): 10036-10043.
DOI: http://dx.doi.org/10.1021/acs.analchem.6b02294
Adapted from press release by University of Freiburg