Antibacterial material restores the efficacy of antibiotics against resistant bacteria
Chalmers University of Technology
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The antibacterial material is a proprietary hydrogel, which can be adapted to many medical applications.
view moreCredit: Photo: Saba Atefyekta
Research from Chalmers University of Technology, Sweden, shows that resistant bacteria can regain susceptibility to antibiotics when the treatment is combined with a material equipped with antibacterial peptides. The study, performed in a laboratory environment, shows that antibiotics can achieve a 64-fold increase in bactericidal effect when used together with the material, whose antibacterial properties are also greatly enhanced by this combination.
The bactericidal material has been developed for medical applications and has been studied by the researchers for many years. It has shown a strong ability to kill many different types of bacteria – including antibiotic-resistant ones. The material consists of a specially designed hydrogel that contains antibacterial peptides, which are molecules that also serve as the building blocks of proteins.
To enable clinical use for the peptide material, particularly in combination with standard treatments such as antibiotics, the researchers had to ensure that the material does not negatively impact the effectiveness of antibiotics when used concurrently.
The study yielded surprisingly positive results: the antibiotics contrariwise became more effective in combination with the material. The researchers also discovered a synergistic effect against certain resistant bacteria, where the antibacterial effects of the peptide material and antibiotics were not only additive but greatly enhanced when used together. This has not been demonstrated before.
"When particles of the hydrogel came into close contact with the bacteria, they weakened and became more susceptible to the antibiotic treatment. In some cases, the antibiotics became effective again against bacteria that were previously resistant," says Annija Stepulane, doctoral student in applied chemistry at Chalmers and the first author of the scientific paper.
Resistant bacteria regained susceptibility
The peptide material was tested in bacterial cultures, in combination with two different antibiotics: oxacillin and vancomycin. The bacteria included in the experiments were two types of staphylococci (S. aureus), one of which is a strain resistant to several antibiotics (MRSA).
The most powerful effect observed in the study was with MRSA, especially when the material was combined with oxacillin – an antibiotic to which the bacteria are normally resistant. The combination lowered the effective concentration of oxacillin 64-fold compared to when the antibiotic was used alone. Consequently, the concentration of oxacillin fell below the threshold at which the bacteria are classified as resistant to the drug.
With vancomycin, the effective concentration was also lowered when the drug was combined with the hydrogel, though this effect was additive rather than synergistic.
Stable and active treatment over time
Researchers have tried to combine antimicrobial peptides with antibiotics previously, but so far only with peptides in solution. In this form, the peptides are highly sensitive and lose effectiveness when exposed to bodily fluids, such as blood. However, when the peptides are attached to a hydrogel, they become significantly more stable and can be active for a longer period.
The Chalmers researchers have previously measured bactericidal activity lasting for several days with the hydrogel, as opposed to a few hours with peptides in solution. They see numerous advantages with this formulation.
"The peptide-based material can be applied locally, on a limited part of the body, so that the entire body is not affected. The material is non-toxic and does not cause any adverse side effects," says Martin Andersson, research leader and professor of applied chemistry at Chalmers.
May curb infections and reduce the risk of complications
The hydrogel, which can also be formulated as particles in a spray, can increase the safety and efficacy of a course of antibiotics that the patient receives. One potential application of this discovery is in wound treatment.
"Often, you don't know whether the bacteria that caused a wound infection are resistant to a certain antibiotic when you start treatment. Applying the peptide material to the wound simultaneously increases the likelihood of the antibiotic being effective against the bacteria. Then you can cure the infection without having to use additional types of antibiotics," says Martin Andersson.
Since the peptide material only has a positive impact on the healing process, the researchers also see great advantages in using it as a standard treatment to prevent wound infections.
"The material could be used in healthcare settings, for example following surgeries – a possibility already available for veterinary care in some countries – and at home. It could function like a regular band-aid, especially for those concerned about infections. This can be particularly interesting in areas with a high prevalence of resistant infections, such as certain parts of Africa and Asia, where extra caution is needed with wound injuries," says Martin Andersson.
More about: the research results and the peptide material
Antimicrobial peptides exist naturally in our bodies and their strong bactericidal properties have been known for a long time. The bacterial cells die because the peptides damage their cell membranes, primarily through an interaction between positive charges in the peptides and negative charges in the bacterial membranes.
Synergistic effects between peptides and antibiotics have been shown previously, but only with free peptides in solution, which are challenging to work with clinically because they break down quickly. The current study is the first to show efficacy with peptides which are bound to a material, making them stable enough for clinical application.
The Chalmers researchers have previously shown that 99.99 percent of skin bacteria are killed by the material and that the bactericidal efficacy is active for more than two days. This enables using the material in many different products, such as wound care materials and coatings on medical devices that are used within the body.
The researchers have theories about the causes of the synergistic effect with antibiotics, but the molecular mechanisms remain to be explored.
More about: research and product development
Research on the antibacterial material is being carried out in close collaboration with the spin-off company Amferia, which is working to commercialize the findings from Chalmers University of Technology.
During this autumn, a wound care dressing with the hydrogel is launched in eight different European countries, intended for veterinary use. An application for approval for a wound care dressing for humans has been submitted for the US market, and the researchers anticipate that it will be available there within a year. The introduction to the European market will take slightly more time due to differing regulations.
The paper Antibacterial efficacy of antimicrobial peptide-functionalized hydrogel particles combined with vancomycin and oxacillin antibiotics has been published in the scientific journal International Journal of Pharmaceutics. The study has been conducted by Annija Stepulane (Chalmers University of Technology), Anand Kumar Rajasekharan (Amferia) and Martin Andersson (Chalmers University of Technology and Amferia).
Annija Stepulane will defend her PhD thesis Soft Amphiphilic Biomaterials for Antibacterial Applications at Chalmers 12 December.
Read more about the research:
Martin Andersson was recently awarded the Chalmers Impact Award 2024
Previous press releases:
New spray fights infections and antibiotic resistance
New material to treat wounds can protect against resistant bacteria
A bacterial cell is simultaneously attacked by antibiotics and a bactericidal material
A bacterial cell (left) is simultaneously attacked on two fronts: by antibiotics and by a positively charged, bactericidal peptide-based material that disrupts the structure of the bacteria’s negatively charged cell membranes. A study from Chalmers University of Technology demonstrates that this combination yields an efficacy far greater than the sum of the individual effects of the antibiotic and the material.
Credit
Illustration: Annija Stepulane/International Journal of Pharmaceutics
WHO World Antimicrobial Resistance Awareness Week
Today, Monday 18 November, the World Health Organization (WHO) begins its annual campaign week to raise awareness and understanding of a serious threat to global public health – antibiotic resistance. World AMR Awareness Week is a global campaign held every year between 18 and 24 November to increase awareness and understanding of antimicrobial resistance, AMR.
Journal
International Journal of Pharmaceutics
Method of Research
Experimental study
Subject of Research
Cells
Article Title
Antibacterial efficacy of antimicrobial peptide-functionalized hydrogel particles combined with vancomycin and oxacillin antibiotics
COI Statement
Annija Stepulane reports equipment, drugs, or supplies and writing assistance were provided by Amferia AB. Martin Andersson reports a relationship with Amferia AB that includes: board membership. Anand Kumar Rajasekharan reports a relationship with Amferia AB that includes: employment. Annija Stepulane reports a relationship with Amferia AB that includes: employment.
Researchers uncover Achilles heel of antibiotic-resistant bacteria
As drug resistance surges, scientists discover a promising new way to control the spread of this public health crisis
University of California - San Diego
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A model structure of a ribosome noted with color-coded flexibility indicators; red highlights ribosome regions that become more flexible, while blue depicts more rigid areas.
view moreCredit: Ashley Moon, Süel Lab, UC San Diego
Recent estimates indicate that deadly antibiotic-resistant infections will rapidly escalate over the next quarter century. More than 1 million people died from drug-resistant infections each year from 1990 to 2021, a recent study reported, with new projections surging to nearly 2 million deaths each year by 2050.
In an effort to counteract this public health crisis, scientists are looking for new solutions inside the intricate mechanics of bacterial infection. A study led by researchers at the University of California San Diego has discovered a vulnerability within strains of bacteria that are antibiotic resistant.
Working with labs at Arizona State University and the Universitat Pompeu Fabra (Spain), Professor Gürol Süel and colleagues in UC San Diego’s School of Biological Sciences investigated the antibiotic resistance of the bacterium Bacillus subtilis. Their research was motivated by the question of why mutant variants of bacteria do not proliferate and take over the population once they have developed an antibiotic-resistant advantage. With an upper hand over other bacteria lacking similar antibiotic resistance, such bacteria should become dominant. Yet they are not. Why?
The answer, reported in the journal Science Advances, is that antibiotic resistance comes at a cost. While antibiotic resistance provides some advantages for the bacteria to survive, the team discovered that it’s also linked with a physiological limitation that hinders potential dominance. This fact, the researchers note, potentially could be exploited to stop the spread of antibiotic resistance.
“We discovered an Achilles heel of antibiotic resistant bacteria,” said Süel, a member of the Department of Molecular Biology at UC San Diego. “We can take advantage of this cost to suppress the establishment of antibiotic resistance without drugs or harmful chemicals.”
Spontaneous mutations of DNA arise in all living cells, including those within bacteria. Some of these mutations lead to antibiotic resistance. Süel and his colleagues focused on physiological mechanisms related to ribosomes, the micro machines within cells that play a key role in synthesizing proteins and translating genetic codes.
All cells rely on charged ions such as magnesium ions to survive. Ribosomes are dependent upon magnesium ions since this metal cation helps stabilize their structure and function. However, atomic-scale modeling during the new research found that mutant ribosome variants that bestow antibiotic resistance excessively compete for magnesium ions with adenosine triphosphate (ATP) molecules, which provide energy to drive living cells. Mathematical models further showed that this results in a ribosome versus ATP tug-of-war over a limited supply of magnesium in the cell.
Studying a ribosome variant within Bacillus subtilis called “L22,” the researchers found that competition for magnesium hinders the growth of L22 more than a normal “wild type” ribosome that is not resistant to antibiotics. Hence the competition levies a physiological toll linked to mutant bacteria with resistance.
“While we often think of antibiotic resistance as a major benefit for bacteria to survive, we found that the ability to cope with magnesium limitation in their environment is more important for bacterial proliferation,” said Süel.
This newly discovered weakness can now be used as a target to counteract antibiotic resistance without the use of drugs or toxic chemicals. For example, it may be possible to chelate magnesium ions from bacterial environments, which should selectively inhibit resistant strains without impacting the wild type bacteria that may be beneficial to our health. “We show that through a better understanding of the molecular and physiological properties of antibiotic-resistant bacteria, we can find novel ways to control them without the use of drugs,” said Süel.
In October Süel and colleagues at the University of Chicago announced a separate approach to combating the antibacterial-resistant bacteria health crisis. Their development of a bioelectronic device that taps into the natural electrical activity of certain bacteria found on our skin paves the way for another drug-free approach to managing infections. The advancement was proven to reduce the harmful effects of Staphylococcus epidermidis, a common bacterium known for causing hospital-acquired infections and contributing to antibiotic resistance. In both studies the researchers used charged ions to control bacteria.
“We are running out of effective antibiotics and their rampant use over the decades has resulted in antibiotics being spread across the globe, from the arctic to the oceans and our groundwater,” said Süel. “Drug-free alternatives to treating bacterial infections are needed and our two most recent studies show how we can indeed achieve drug-free control over antibiotic resistant bacteria.”
The authors of the new study were: Eun Chae Moon, Tushar Modi, Dong-yeon Lee, Danis Yangaliev, Jordi Garcia-Ojalvo, S. Banu Ozkan and Gürol Süel.
Image depicts the outlines of bacterial cells with green fluorescence highlighting a lack of magnesium.
Credit
Ashley Moon, Süel Lab, UC San Diego
A magnified view of the ribosome variant within Bacillus subtilis known as L22 (black) and surrounding magnesium ions (green dots).
Credit
Ashley Moon, Süel Lab, UC San Diego
Journal
Science Advances
Method of Research
Experimental study
Subject of Research
Cells
Article Title
Physiological cost of antibiotic resistance: Insights from a ribosome variant in bacteria
Article Publication Date
15-Nov-2024
Outsmarting superbugs resistant to antibiotics
$3.96 million to UH College of Pharmacy to find combination therapies
University of Houston
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NIH has awarded $3.96 million to Vincent Tam, professor of Pharmacy Practice and Translational Research at the University of Houston College of Pharmacy.
view moreCredit: University of Houston
Gram-negative bacteria pose a serious threat to global health because they can resist multiple antibiotics, making infections difficult to treat, according to the National Institutes of Health. In response, the NIH has awarded $3.96 million to Vincent Tam, professor of Pharmacy Practice and Translational Research at the UH College of Pharmacy, to outsmart these superbugs by designing more effective combination therapies that can overcome their defenses.
Tam will develop a cutting-edge monitoring device and data-processing algorithm that will guide the design of combination therapy.
“The rate of new drug development is unlikely to keep pace with the increase in multidrug resistance, so a robust method to guide rational selection of combination therapy would be crucial to delay returning to the pre-antibiotic era,” said Tam. “Our long-term goal is to optimize clinical use of antibiotics to combat the emergence of resistance.”
The threat
Gram-negative infections have become increasingly difficult to treat and often arise among hospital patients, causing urinary tract infections, pneumonia, bloodstream infections, wound or surgical infections and meningitis.
Gram-negative bacteria are built to be hard to fight, enclosed in a protective capsule, that prevents white blood cells – that fight infection - from ingesting the bacteria. Then, when the hard-to-fight bacteria do die, they release toxins from their outer membrane, which can trigger inflammation, fever or even septic shock.
“Upon completion of our research, clinicians could be guided in the selection of combination therapy, without comprehensive knowledge of the resistance mechanisms involved,” said Tam.
The plan
Tam plans to first identify useful antibiotic combinations against multidrug resistant bacteria and then validate the mathematical model predictions with clinical outcomes. He will use three highly resistant gram-negative strains - P. aeruginosa, A. baumannii and K. pneumoniae - for his research.
“However, the proposed model-based system is not confined to a specific antimicrobial agent - pathogen combination. It could be extrapolated to other antimicrobial agents (e.g., antibacterials, antifungals and antiretrovirals) with different mechanisms of action, as well as to other pathogens (e.g., Neisseria gonorrhoeae, Candida auris, and HIV) with different microbiological characteristics,” said Tam.
At UH, Michael Nikolaou, professor of chemical and biomolecular engineering, is a co-investigator of the award. Other co-investigators are William Musick, Houston Methodist Hospital and Truc Cecilia Tran, Houston Methodist Research Institute.
Scientists uncover new mechanism in bacterial DNA enzyme opening pathways for antibiotic development
Durham University
Researchers from Durham University, Jagiellonian University (Poland) and the John Innes Centre have achieved a breakthrough in understanding DNA gyrase, a vital bacterial enzyme and key antibiotic target.
This enzyme, present in bacteria but absent in humans, plays a crucial role in supercoiling DNA, a necessary process for bacterial survival.
Using high-resolution cryo-electron microscopy the researchers reveal unprecedented detail of gyrase’s action on DNA, potentially opening doors for new antibiotic therapies against resistant bacteria.
The research is published in Proceedings of the National Academy of Sciences (PNAS).
DNA gyrase operates like a tiny molecular machine, carefully twisting and stabilising bacterial DNA. This twisting, known as supercoiling, is similar to winding an elastic band: as it twists, it coils tighter and tighter.
Unlike a band that would unwind if released, DNA gyrase stabilises DNA’s twisted form, making it functional for bacteria.
The enzyme wraps DNA in a ‘figure-of-eight’ loop, then precisely breaks and passes strands through each other, resealing them afterward. This is a delicate process—if the DNA remained broken, it would be lethal to the bacteria.
Antibiotics such as fluoroquinolones exploit this vulnerability by preventing the DNA resealing, which kills the bacterial cell. However, resistance to these antibiotics is growing, so a deeper understanding of how gyrase functions is urgently needed.
Using state-of-the-art cryo-electron microscopy, the team captured a snapshot of gyrase at work, revealing how it wraps DNA through outstretched protein arms to form the figure-of-eight shape.
This finding updates the conventional view of gyrase’s mechanism, which has been studied for decades. The images show the enzyme as a highly coordinated, multi-part system, with each piece moving in a precise sequence to achieve DNA supercoiling.
Reflecting on the study findings, co-author Professor Jonathan Heddle of Durham University said: “The results suggested the exact position and the order of the complex moving parts of the enzyme during when the supercoiling process occurs were not quite as we previously thought, and this could impact how we design new inhibitors.”
This discovery not only advances our knowledge of bacterial biology but also holds promise for new antibiotics designed to block gyrase in a more targeted way, bypassing existing resistance mechanisms.
With this high-resolution structure as a guide, researchers aim to take additional snapshots of the enzyme in various stages, building a molecular movie of how gyrase works.
This detailed approach could aid in the development of next-generation antibiotics that are more precise and effective in stopping bacterial infections.
Journal
Proceedings of the National Academy of Sciences
Article Title
Structural basis of chiral wrap and T-segment capture by Escherichia coli DNA gyrase’
Article Publication Date
25-Nov-2024
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