Tag Archives: Antibiotics

Study Shows Healthy Dogs and Cats Can Transmit Dangerous Microbes to Humans – And Vice Versa

Multi-drug-resistant organisms can be transmitted between healthy dogs and cats and their hospitalized owners.

Fortunately, only a small number of cases were found suggesting pets are not a major source of antibiotic-resistant infections in hospital patients.

Healthy dogs and cats could be passing on multidrug-resistant organisms (MDROs; bacteria that resist treatment with more than one antibiotic) to their hospitalized owners, and likewise, humans could be transmitting these dangerous microbes to their pets, according to new research being presented at this year’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Copenhagen, Denmark (April 15-18).

The study of over 2,800 hospital patients and their companion animals is by Dr. Carolin Hackmann from Charité University Hospital Berlin, Germany, and colleagues.

“Our findings verify that the sharing of multidrug-resistant organisms between companion animals and their owners is possible,” says Dr. Hackmann. “However, we identified only a handful of cases suggesting that neither cat nor dog ownership is an important risk factor for multidrug-resistant organism colonization in hospital patients.”

The role of pets as potential reservoirs of MDROs is a growing concern worldwide. Antimicrobial resistance happens when infection-causing microbes (such as bacteria, viruses, or fungi) evolve to become resistant to the drug designed to kill them. Estimates suggest that antimicrobial-resistant infections caused almost 1.3 million deaths and were associated with nearly 5 million deaths around the world in 2019.[1]

In this case control study, researchers wanted to find out whether pets (ie, cats and dogs) play a role in the infection of hospital patients with MDROs.

They focused on the most common superbugs in hospital patients—methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), 3rd generation cephalosporin-resistant Enterobacterales (3GCRE) and carbapenem-resistant Enterobacterales (CRE), which are resistant to multiple antibiotics including penicillin and cephalosporins.

Between June 2019 and September 2022, nasal and rectal swabs were collected from 2,891 patients hospitalized in Charité University Hospital Berlin (1,184 patients with previous colonization or colonization on admission and 1,707 newly admitted patients as controls), and from any dogs and cats that lived in their households.

Genetic sequencing was used to identify both the species of bacteria in each sample, and the presence of drug-resistance genes. Whole genome sequencing was used to confirm the possible sharing of resistant bacteria.

Participants were also asked about well-known risk factors for MDROs (e.g., recent MDRO infections or use of antibiotics, recent hospital stays, presence of urinary or central venous catheters), as well as information about the number of pets in the household, the closeness of contact, and pet health.

Overall, 30% (871/2,891) of hospital patients tested positive for MDROs, and 70% (2,020/2,891) tested negative. The rate of dog ownership was 11% (93/871) and cat ownership 9% (80/871) in those who tested MDRO-positive, and 13% (267/2,020 and 253/2,020 respectively) in MDRO-negatives.

All 626 pet owners were asked to send throat and stool swab samples of their pets. Overall, 300 pet owners sent back samples from 400 pets. Of these samples, 15% (30/203) of dogs and 5% (9/197) of cats tested positive for at least one MDRO. In four cases, MDROs were phenotypically matching (MDROs were the same species and showed the same antibiotic resistance) between pets and their owners.

Whole genome sequencing confirmed that only one of the matching pairs was genetically identical in a dog and its owner. The matching pathogen was 3GCR Escherichia coli (common in the intestines of healthy people and animals).

“Although the level of sharing between hospital patients and their pets in our study is very low, carriers can shed bacteria into their environment for months, and they can be a source of infection for other more vulnerable people in the hospital such as those with a weak immune system and the very young or old,” says Dr. Hackmann.

This is an observational study and cannot prove that close contact with pets causes colonization with MDROs, but only suggest the possibility of co-carriage, while the direction of transfer is unclear. The authors point to several limitations, including a possible under-reporting of MDRO colonization in pets due to problems in taking swab samples, which was done by the pet owners themselves. Finally, the study results apply to the setting of hospital patients in an urban area and therefore may not be applicable to the general population or MDRO high-risk groups like livestock farmers.


Meeting: European Society of Clinical Microbiology and Infectious Diseases (ECCMID) 2023

A New Treatment for Lung Infections: Scientists Have Created a Unique “Living Medicine”

Scientists have created the first “living medicine” to cure lung infections. This innovative treatment is aimed at Pseudomonas aeruginosa, a bacteria known for its resistance to many antibiotics and a frequent cause of infections in hospitals.

This treatment involves the use of a modified form of the Mycoplasma pneumoniae bacterium, which has had its disease-causing abilities removed and reprogrammed to target P. aeruginosa. The modified bacterium is used in conjunction with low doses of antibiotics that would not be effective on their own.

Researchers tested the efficacy of the treatment in mice, finding that it significantly reduced lung infections. The “living medicine” doubled mouse survival rate compared to not using any treatment. Administering a single, high dose of the treatment showed no signs of toxicity in the lungs. Once the treatment had finished its course, the innate immune system cleared the modified bacteria in a period of four days.

The findings are published in the journal Nature Biotechnology and were funded by the “la Caixa” Foundation through the CaixaResearch Health call. The study was led by researchers at the Centre for Genomic Regulation (CRG) and Pulmobiotics in collaboration with the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona and the Institute of Agrobiotechnology (IdAB), a joint research institute of Spain’s CSIC and the government of Navarre.

P. aeruginosa infections are difficult to treat because the bacteria live in communities that form biofilms. Biofilms can attach themselves to various surfaces in the body, forming impenetrable structures that escape the reach of antibiotics.

P. aeruginosa biofilms can grow on the surface of endotracheal tubes used by critically-ill patients who require mechanical ventilators to breathe. This causes ventilator-associated pneumonia (VAP), a condition that affects one in four (9-27%) patients who require intubation. The incidence exceeds 50% for patients intubated because of severe Covid-19. VAP can extend the duration in the intensive care unit for up to thirteen days and kills up to one in eight patients (9-13%).

The authors of the study engineered M. pneumoniae to dissolve biofilms by equipping it with the ability to produce various molecules including pyocins, toxins naturally produced by bacteria to kill or inhibit the growth Pseudomonas bacterial strains. To test its efficacy, they collected P. aeruginosa biofilms from the endotracheal tubes of patients in intensive care units. They found the treatment penetrated the barrier and successfully dissolved the biofilms.

“We have developed a battering ram that lays siege to antibiotic-resistant bacteria. The treatment punches holes in their cell walls, providing crucial entry points for antibiotics to invade and clear infections at their source. We believe this is a promising new strategy to address the leading cause of mortality in hospitals,” says Dr. María Lluch, Chief Scientific Officer at Pulmobiotics, co-corresponding author of the study and principal investigator at the International University of Catalonia.

With the aim of using “living medicine” to treat VAP, the researchers will carry out further tests before reaching the clinical trial phase. The treatment is expected to be administered using a nebulizer, a device that turns liquid medicine into a mist which is then inhaled through a mouthpiece or a mask.

M. pneumoniae is one of the smallest known species of bacteria. Dr. Luis Serrano, Director of the CRG, first had the idea to modify the bacteria and use it as a ‘living medicine’ two decades ago. Dr. Serrano is a specialist in synthetic biology, a field that involves repurposing organisms and engineering them to have new, useful abilities. With just 684 genes and no cell wall, the relative simplicity of M. pneumoniae makes it ideal for engineering biology for specific applications.

One of the advantages of using M. pneumoniae to treat respiratory diseases is that it is naturally adapted to lung tissue. After administering the modified bacterium, it travels straight to the source of a respiratory infection, where it sets up shop like a temporary factory and produces a variety of therapeutic molecules.

By showing that M. pneumoniae can tackle infections in the lung, the study opens the door for researchers to create new strains of the bacteria to tackle other types of respiratory diseases such as lung cancer or asthma. “The bacterium can be modified with a variety of different payloads – whether these are cytokines, nanobodies, or defensins. The aim is to diversify the modified bacterium’s arsenal and unlock its full potential in treating a variety of complex diseases,” says ICREA Research Professor Dr. Luis Serrano.

In addition to designing the ‘living medicine’, Dr. Serrano’s research team is also using their expertise in synthetic biology to design new proteins that can be delivered by M. pneumoniae. The team is using these proteins to target inflammation caused by P. aeruginosa infections.

Though inflammation is the body’s natural response to an infection, excessive or prolonged inflammation can damage lung tissue. The inflammatory response is orchestrated by the immune system, which releases mediator proteins such as cytokines. One type of cytokine – IL-10 – has well-known anti-inflammatory properties and is of growing therapeutic interest.

Research published in the journal Molecular Systems Biology by Dr. Serrano’s research group used protein-design softwares ModelX and FoldX to engineer new versions of IL-10 purposefully optimized to treat inflammation. The cytokines were designed to be created more efficiently and to have a higher affinity, meaning less cytokines are needed to have the same effect.

The researchers engineered strains of M. pneumoniae that expressed the new cytokines and tested its efficacy in the lungs of mice with acute P. aeruginosa infections. They found that engineered versions of IL-10 were significantly more effective at reducing inflammation compared to the wild-type IL-10 cytokine.

According to Dr. Ariadna Montero Blay, co-corresponding author of the study in Molecular Systems Biology, “live biotherapeutics such as M. pneumoniae provide ideal vehicles to help overcome the traditional limitations of cytokines and unlock their huge potential in treating a variety of human diseases. Engineering cytokines as therapeutic molecules was critical to tackle inflammation. Other lung diseases such as asthma or pulmonary fibrosis could also stand to benefit from this approach.”

Reference: “Engineered live bacteria suppress Pseudomonas aeruginosa infection in mouse lung and dissolve endotracheal-tube biofilms” by Rocco Mazzolini, Irene Rodríguez-Arce, Laia Fernández-Barat, Carlos Piñero-Lambea, Victoria Garrido, Agustín Rebollada-Merino, Anna Motos, Antoni Torres, Maria Jesús Grilló, Luis Serrano and Maria Lluch-Senar, 19 January 2023, Nature Biotechnology.
DOI: 10.1038/s41587-022-01584-9

Killing Even Antibiotic-Resistant Bacteria: A New Infection-Fighting Wound Spray

The World Health Organization (WHO) has listed antibiotic resistance as a top ten global health threat, making it imperative to find new ways to combat resistant bacteria and decrease the reliance on antibiotics. In response to this pressing issue, researchers at the Chalmers University of Technology in Sweden have developed a new spray that has the ability to kill even antibiotic-resistant bacteria. This innovative solution can be used for wound care and directly on medical devices such as implants.

“Our innovation can have a dual impact in the fight against antibiotic resistance. The material has been shown to be effective against many different types of bacteria, including those that are resistant to antibiotics, such as Methicillin-resistant Staphylococcus aureus (MRSA), while also having the potential to prevent infections and thus reduce the need for antibiotics,” says Martin Andersson, head of research for the study and professor at the Department of Chemistry and Chemical Engineering at Chalmers.

It is already estimated that antibiotic-resistant bacteria cause nearly 1.3 million deaths a year worldwide. As part of the effort to slow down the spread and development of drug resistance, researchers at Chalmers are developing a new antibacterial material that can be used in healthcare and become an effective tool to fight antibiotic resistance.

The material consists of small hydrogel particles equipped with a type of peptide that effectively kills and binds bacteria. Attaching the peptides to the particles provides a protective environment and increases the stability of the peptides. This allows them to work together with body fluids such as blood, which otherwise inactivates the peptides, making them difficult to use in healthcare. In previous studies, the researchers showed how the peptides can be used for wound care materials such as wound dressings.

They have now published two new studies in which the bactericidal material is used in the form of a wound spray and as a coating on medical devices that are introduced into our bodies. This new step in the research means that the innovation can be used in more ways and be of even greater benefit in healthcare.

The wound spray, which can reach into deep wounds and other open areas on the body where bacteria can enter, is flexible and very useful for treating and preventing infection. The new material has many advantages over existing sprays and disinfectants

“The substance in this wound spray is completely non-toxic and does not affect human cells. Unlike existing bactericidal sprays, it does not inhibit the body’s healing process. The materials, which are simply sprayed onto the wound, can also kill the bacteria in a shorter time,” says Edvin Blomstrand, an industrial doctoral student at the Department of Chemistry and Chemical Engineering at Chalmers University of Technology and one of the lead authors of the scientific article.

For treatments in which materials such as implants and catheters are inserted into our bodies, infections are a major problem. Therefore, there is a great need for new antibacterial biomaterials, i.e. materials that treat, replace or modify organs, tissue, or functions in a biological body. One of the major sources of hospital-acquired infection comes from the usage of urinary catheters. The Chalmers researchers’ new coating can now be an effective new tool for reducing this risk and preventing infections.

“Although the catheters are sterile when unpacked, they can become contaminated with bacteria while they are being introduced into the body, which can lead to infection. One major advantage of this coating is that the bacteria are killed as soon as they come into contact with the surface. Another is that it can be applied to existing products that are already used in healthcare, so it is not necessary to produce new ones,” says Annija Stepulane, a doctoral student at the Department of Chemistry and Chemical Engineering at Chalmers and one of the lead authors of the article.

In the study, the researchers tested the coating on silicone materials used for catheters, but they see opportunities to use it on other biomaterials.

The research on the antibacterial materials is being conducted in collaboration with the spin-off company Amferia AB, which is also commercializing the technology. Chalmers and Amferia have previously presented the antibacterial material in the form of hydrogel wound dressings, which are presently under clinical investigation for both human and animal wound care.

The beneficial properties of antimicrobial peptides have been known for many years. They exist in thousands of different variants in the natural immune systems of humans, animals, and plants, and researchers have long sought to mimic and harness the peptides to prevent and treat infections. In their natural state, these peptides are rapidly broken down when they come into contact with body fluids such as blood, which makes their direct clinical use difficult. In the materials the researchers are developing, they have solved this problem by binding the peptides to particles. For both the spray and the coating, they have been able to measure that the bactericidal effect of the materials lasts for up to 48 hours in contact with body fluids and as long as a few years without contact with body fluids.

The researchers have shown that 99.99 percent of bacteria are killed by the material and that the bactericidal capacity is active for approximately 48 hours, enabling its use in a wide range of clinical applications. Since the materials are non-toxic, they can be used directly on or in the body, preventing or curing an infection without adversely affecting the natural healing process.

References: “Cross-linked lyotropic liquid crystal particles functionalized with antimicrobial peptides” by Edvin Blomstrand, Anand K. Rajasekharan, Saba Atefyekta and Martin Andersson, 22 September 2022, International Journal of Pharmaceutics.
DOI: 10.1016/j.ijpharm.2022.122215

“Multifunctional Surface Modification of PDMS for Antibacterial Contact Killing and Drug-Delivery of Polar, Nonpolar, and Amphiphilic Drugs” by Annija Stepulane, Anand Kumar Rajasekharan and Martin Andersson, 2 November 2022, ASC Applied Bio Materials.
DOI: 10.1021/acsabm.2c00705

Antibiotics can destroy many types of bacteria, but increasingly, bacterial pathogens are gaining resistance to many commonly used …

Antibiotics can destroy many types of bacteria, but increasingly, bacterial pathogens are gaining resistance to many commonly used types. As the threat of antibiotic resistance looms large, researchers have sought to find new antibiotics and other ways to destroy dangerous bacteria. But new antibiotics can be extremely difficult to identify and test. Bacteriophages, which are viruses that only infect bacterial cells, might offer an alternative. Bacteriophages (phages) were studied many years ago, before the development of antibiotic drugs, and they could help us once again.

Image credit: Pixabay

If we are going to use bacteriophages in the clinic to treat humans, we should understand how they work, and how bacteria can also become resistant to them. Microbes are in an arms race with each other, so while phages can infect bacteria, some bacterial cells have found ways to thwart the effects of those phages. New research reported in Nature Microbiology has shown that when certain bacteria carry a specific genetic mutation, phages don’t work against them anymore.

In this study, the researchers used a new technique so they could actually see a phage attacking bacteria. Mycobacteriophages infect Mycobacterial species, including the pathogens Mycobacterium tuberculosis and Mycobacterium abscessus, as well as the harmless Mycobacterium smegmatis, which was used in this research.

The scientists determined that Mycobacterial gene called lsr2 is essential for many mycobacteriophages to successfully infect Mycobacteria. Mycobacteria that carry a mutation that renders the Lsr2 protein non-functional are resistant to these phages.

Normally, Lsr2 aids in DNA replication in bacterial cells. Bacteriophages can harness this protein, however, and use it to reproduce the phage’s DNA. Thus, when Lsr2 stops working, the phage cannot replicate and it cannot manipulate bacterial cells.

In the video above, by first study author Charles Dulberger, a genetically engineered mutant phage infects Mycobacterium smegmatis. First, one phage particle (red dot at 0.42 seconds) binds to a bacterium. The phage DNA (green fluorescence) is injected into the bacterial cell (2-second mark). The bright green dots at the cells’ ends are not relevant. For a few seconds, the DNA forms a zone of phage replication, and fills the cell. Finally, the cell explodes at 6:25 seconds. (About three hours have been compressed to make this video.)

The approach used in this study can also be used to investigate other links between bacteriophages and the bacteria they infect.

“This paper focuses on just one bacterial protein,” noted co-corresponding study author Graham Hatfull, a Professor at the University of Pittsburgh. But there are many more opportunities to use this technique. “There are lots of different phages and lots of other proteins.”

Sources: University of Pittsburgh, Nature Microbiology

Carmen Leitch

A Hidden Hazard: Antibiotic Residues in Water Pose a Threat to Human Health

A comprehensive study from Karolinska Institute, published in The Lancet Planetary Health, warns that the presence of antibiotic residue in wastewater and treatment plants in the regions nearby China and India could fuel antibiotic resistance and the drinking water could pose a danger to human health.

Additionally, the researchers determined the relative contribution of different sources of antibiotic contamination in waterways, including hospitals, municipal areas, livestock farming, and pharmaceutical production.

”Our results can help decision-makers to target risk reduction measures against environmental residues of priority antibiotics and in high-risk sites, to protect human health and the environment,” says Nada Hanna, a researcher at the Department of Global Public Health at Karolinska Institute in Sweden, and the study’s first author. “Allocating these resources efficiently is especially vital for resource-poor countries that produce large amounts of antibiotics.”

Bacteria that become resistant to antibiotics are a global threat that can lead to untreatable bacterial infections in animals and humans.

Antibiotics can enter the environment during their production, consumption, and disposal. Antibiotic residues in the environment, such as in wastewater and drinking water, can contribute to the emergence and spread of resistance.

The researchers have examined the levels of antibiotic residues that are likely to contribute to antibiotic resistance from different aquatic sources in the Western Pacific Region (WPR) and the South-East Asia Region (SEAR), regions as defined by the World Health Organization. These regions include China and India, which are among the world’s largest producers and consumers of antibiotics.

This was done by a systematic review of the literature published between 2006 and 2019, including 218 relevant reports from the WPR and 22 from the SEAR. The researchers also used a method called Probabilistic Environmental Hazard Assessment to determine where the concentration of antibiotics is high enough to likely contribute to antibiotic resistance.

Ninety-two antibiotics were detected in the WPR, and forty-five in the SEAR. Antibiotic concentrations exceeding the level considered safe for resistance development (Predicted No Effect Concentrations, PNECs) were observed in wastewater, influents, and effluents of wastewater treatment plants and in receiving aquatic environments. The highest risk was observed in wastewater and influent of wastewater treatment plants. The relative impact of various contributors, such as hospital, municipal, livestock, and pharmaceutical manufacturing was also determined.

In receiving aquatic environments, the highest likelihood of levels exceeding the threshold considered safe for resistance development was observed for the antibiotic ciprofloxacin in drinking water in China and the WPR.

”Antibiotic residues in wastewater and wastewater treatment plants may serve as hot spots for the development of antibiotic resistance in these regions and pose a potential threat to human health through exposure to different sources of water, including drinking water,” says Nada Hanna.

Reference: “Antibiotic concentrations and antibiotic resistance in aquatic environments of the WHO Western Pacific and South-East Asia regions: a systematic review and probabilistic environmental hazard assessment” by Nada Hanna, Ph.D., Prof Ashok J Tamhankar, Ph.D. and Prof Cecilia Stålsby Lundborg, Ph.D., January 2023, The Lancet Planetary Health.
DOI: 10.1016/S2542-5196(22)00254-6

Limitations to be considered when interpreting the results are the lack of data on the environmental occurrence of antibiotics from many of the countries in the regions and the fact that only studies written in English were included.

The research has been funded by the Swedish Research Council. The researchers declare no competing interests.

Gut Bugs: The Microbes Responsible for Controlling Your Body’s Temperature

Normal body temperature can vary from individual to individual. However, despite this variation, the average basal body temperature of humans has mysteriously dropped since the 1860s. A recent study points to the gut microbiome as a possible contributor to regulating body temperature, both in healthy individuals and during life-threatening infections.

The study, conducted by a team of researchers led by Robert Dickson, M.D., at the University of Michigan Medical School, utilized health records from patients admitted to the hospital with sepsis and conducted experiments on mice to investigate the relationship between the gut bacteria composition, temperature changes, and health outcomes.

Sepsis, the body’s response to a life-threatening infection, can cause drastic changes in body temperature, the trajectory of which is linked to mortality. Previous work has demonstrated that hospitalized patients with sepsis vary widely in their temperature responses, and this variation predicts their survival.

“There’s a reason that temperature is a vital sign,” said Kale Bongers M.D. Ph.D., a clinical instructor in the Department of Internal Medicine and lead author of the study. “It’s both easily measured and tells us important information about the body’s inflammatory and metabolic state.”

Yet the causes of this temperature variation, both in sepsis and in health, have remained unknown.

“We know that temperature response is important in sepsis because it strongly predicts who lives and who dies,” said Dickson. “But we don’t know what drives this variation and whether it can be modified to help patients.”

To try to understand the cause of this variation, the team analyzed rectal swabs from 116 patients admitted to the hospital. The patients’ gut microbiota varied widely, confirming that it is a potential source of variation.

“Arguably, our patients have more variation in their microbiota than they do in their own genetics,” said Bongers. “Any two patients are more than 99% identical in their own genomes, while they may have literally 0% overlap in their gut bacteria.”

The authors found that this variation in gut bacteria was correlated with patients’ temperature trajectories while in the hospital. In particular, common bacteria from the Firmicutes phylum were most strongly associated with increased fever response. These bacteria are common, variable across patients, and are known to produce important metabolites that enter the bloodstream and influence the body’s immune response and metabolism.

To confirm these findings under controlled conditions, the team used mouse models, comparing normal mice with genetically identical mice that lack a microbiome. Experimental sepsis caused dramatic changes in the temperature of conventional mice but had a blunted effect on the temperature response of germ-free mice. Among mice with a microbiome, variation in temperature response was strongly correlated with the same bacterial family (Lachnospiraceae) that was found in humans.

“We found that the same kind of gut bacteria explained temperature variation both in our human subjects and in our laboratory mice,” said Dickson. “This gave us confidence in the validity of our findings and gives us a target for understanding the biology behind this finding.”

Even in health, mice without a microbiome had lower basal body temperatures than conventional mice. Treating normal mice with antibiotics also reduced their body temperature.

The study highlights an underappreciated role of the gut microbiome in body temperature and could explain the reduction in basal body temperature over the past 150 years.

“While we certainly haven’t proven that changes in the microbiome explain the drop in human body temperature, we think it is a reasonable hypothesis,” said Bongers. “Human genetics haven’t meaningfully changed in the last 150 years, but changes in diet, hygiene, and antibiotics have had profound effects on our gut bacteria.”

Further research is needed to understand whether targeting the microbiome to modulate body temperature could help alter the outcome for patients with sepsis.

Reference: “The Gut Microbiome Modulates Body Temperature Both in Sepsis and Health” by Kale S. Bongers, Rishi Chanderraj, Robert J. Woods, Roderick A. McDonald, Mark D. Adame, Nicole R. Falkowski, Christopher A. Brown, Jennifer M. Baker, Katherine M. Winner, Daniel J. Fergle, Kevin J. Hinkle, Alexandra K. Standke, Kimberly C. Vendrov, Vincent B. Young, Kathleen A. Stringer, Michael W. Sjoding and Robert P. Dickson, 23 January 2023, American Journal of Respiratory and Critical Care Medicine.
DOI: 10.1164/rccm.202201-0161OC

Partners can accomplish amazing things, and it seems that is true for bacteria. Large colonies of bacteria called …

Partners can accomplish amazing things, and it seems that is true for bacteria. Large colonies of bacteria called biofilms become very resilient and can even gain new abilities. New research has shown that different types of bacteria can even work cooperatively to become more powerful. Scientists have revealed a collaborative relationship between Klebsiella pneumoniae and Acinetobacter baumannii, bacterial pathogens that can cause illnesses including pneumonia and urinary tract infections. They can even cause deadly infections of the bloodstream.

An SEM image of a human neutrophil (blue) interacting with two multidrug-resistant (MDR), Klebsiella pneumoniae bacteria (pink), which are known to cause severe hospital acquired, nosocomial infections. / Credit: National Institute of Allergy and Infectious Diseases (NIAID) / David Dorward; Ph.D.; NIAID

Both of these microbial pathogens have been highlighted by the World Health Organization because new antibiotics are needed to fight them. They are often identified in so-called polymicrobial infections, in which combinations of bacteria, fungi, parasites, and viruses cause illness. They are also a common problem in hospital-acquired infections.

This study has shown that Klebsiella produces metabolic byproducts that provide nutrition to Acinetobacter, and in return, Acinetobacter acts as a shield, releasing enzymes that degrade Klebsiella-destroying antibiotics. A combination of methods from various fields including microbiology, microscopy, and genetics were used in this effort; it illustrated an example of syntrophy, in which bacterial species are in a mutually symbiotic relationship, with one consuming the byproducts of another. The findings have been reported in Nature Communications.

In this research, the investigators analyzed strains of microbes isolated from a co-infection, and used an animal model to reveal “a mutually beneficial relationship” between Klebsiella and Acinetobacter. This allows Klebsiella to survive significantly higher antibiotic concentrations significantly than it would by itself, said Dr. Lucie Semenec of Macquarie University.

Co-lead study author Associate Professor Amy Cain of Macquarie University noted that the findings highlight the importance of screening for polymicrobial infections in clinical settings, because together, these pathogens are more dangerous and they feed off one another.

“This research is significant because diagnostic methods commonly look for the most dominant pathogen and therefore treatment is targeted at that,” noted Semenec. “New drugs now can be informed in future research by the molecular mechanisms we find in this work.”

Sources: Macquarie University, Nature Communications

Carmen Leitch

A New Potential Method To Treat Superbug Infections

Scientists at the University of Galway have uncovered a way to enhance the effectiveness of penicillin-type antibiotics against MRSA, a dangerous superbug. Their findings have the potential to improve MRSA treatment options as penicillin-type antibiotics are currently ineffective on their own.

The study, led by the University of Galway’s Professor James P O’Gara and Dr. Merve S Zeden, was recently published in the journal mBio

Professor of Microbiology James O’Gara said: “This discovery is important because it has revealed a potentially new way to treat MRSA infections with penicillin-type drugs, which remain the safest and most effective antibiotics.”

The antimicrobial resistance (AMR) crisis is one of the greatest threats to human health with superbugs like MRSA placing a significant burden on global healthcare resources.

The microbiology research team at the University of Galway showed that MRSA could be much more efficiently killed by penicillin-type antibiotics when combined with purines, which are the building blocks for DNA.

Dr. Zeden said: “Purine nucleosides, Adenosine, Xanthosine, and Guanosine are sugar versions of the building blocks of DNA, and our work showed that they interfere with signaling systems in the bacterial cell which are required for antibiotic resistance.”

The discussion noted the drugs derived from purines are already used to treat some viral infections and cancers.

Aaron Nolan is a Ph.D. student at the University of Galway and was the co-first author on the paper. He said: “Finding new ways to re-sensitize superbugs to currently licensed antibiotics is a crucial part of efforts to tackle the AMR crisis. Our research implicated the potential of purine nucleosides in re-sensitizing MRSA to penicillin-type antibiotics.”

Reference: “Purine Nucleosides Interfere with c-di-AMP Levels and Act as Adjuvants To Re-Sensitize MRSA To β-Lactam Antibiotics” by Aaron C. Nolan, Merve S. Zeden, Igor Kviatkovski, Christopher Campbell, Lucy Urwin, Rebecca M. Corrigan, Angelika Gründling and James P. O’Gara, 12 December 2022, mBio.
DOI: 10.1128/mbio.02478-22

The study was funded by the Health Research Board, Science Foundation Ireland, and the Irish Research Council.


Simple Intervention Greatly Decreases Mothers’ Risk of Death During Childbirth

A sweeping new international study has found that a single dose of the antibiotic azithromycin can help protect mothers from dangerous sepsis infections and death during vaginal childbirth. Published in the New England Journal of Medicine, the study was conducted by a UVA Health scientist and his collaborators.

Azithromycin, also known as Z-Pak, has already been shown to benefit women delivering by cesarean section. But the new findings reveal that the common antibiotic reduces mortality for women delivering vaginally and cuts their risk of developing sepsis, a potentially fatal full-body infection.

Infections, particularly sepsis, are responsible for 10% of maternal deaths shortly before, during, and after childbirth, putting such infections in the top five causes of maternal mortality worldwide.

“A single dose of the antibiotic azithromycin decreased sepsis and death by half in women in labor,” said researcher William A. Petri Jr., MD, PhD, of the University of Virginia School of Medicine’s Division of Infectious Diseases and International Health. “The simplicity of this intervention should allow its institution around the globe to protect mothers during childbirth.”

Petri is part of the Azithromycin Prophylaxis in Labor Use Study (A-PLUS) Trial Group, an international coalition of researchers that set out to determine if giving the antibiotic during childbirth would benefit either mothers or their children. More than 29,000 women in low- and middle-income countries volunteered to take part in the randomized trial; half were given azithromycin and half were given a harmless placebo.

Among the 14,637 women who received the placebo, 2.4% developed sepsis or died within six weeks. That’s compared with only 1.6% of the 14,526 women who received azithromycin. The difference was clear enough that the researchers stopped the trial early.

The antibiotic did not provide similar benefits for the babies, the researchers found. However, they say that benefits for the mothers, combined with the lack of harmful side effects, makes azithromycin an important new tool for keeping moms safe before, during, and after delivery. (The antibiotic is already recommended for caesarian births in the United States and elsewhere.)

UVA is one of seven universities participating in the Global Network for Women’s and Children’s Health, which is supported by a grant from the National Institute of Child Health and Human Development. Network research supports and conducts clinical trials in resource-limited countries by pairing foreign and U.S. investigators, with the goal of evaluating low-cost, sustainable interventions to improve maternal and child health and simultaneously building local research capacity and infrastructure.

The network team at UVA includes Petri, Drs. Chris Chisholm (Obstetrics/Gynecology), Rob Sinkin (Pediatrics), Chelsea Braun (Medicine/Infectious Diseases) and Program Manager Lauren Swindell and in Bangladesh Drs. Rashidul Haque and Masum Billah of the icddr,b research center, and Ruth Lennox of the LAMB Hospital.

Petri noted that the findings result from an important collaboration of scientists around the world working together to improve care for pregnant women and help them deliver their babies more safely.

“All of us engaged in the work of the network here in Charlottesville are enjoying the opportunity to collaborate across disciplines, each of us enriched by the perspectives of obstetricians, pediatricians, and infectious-diseases specialists,” Petri said. “The network is open to all to propose new multi-site international studies in maternal and child health, and I hope that innovative ideas and ultimately clinical trials will originate here at UVA.”

The researchers have published their findings in the prestigious New England Journal of Medicine. A full list of the authors and their affiliations is included in the paper.

Reference: “Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth” by Alan T.N. Tita, M.D., Ph.D., Waldemar A. Carlo, M.D., Elizabeth M. McClure, Ph.D., Musaku Mwenechanya, M.D., Elwyn Chomba, M.B., Ch.B., Jennifer J. Hemingway-Foday, M.P.H., Avinash Kavi, M.D., Mrityunjay C. Metgud, M.D., Shivaprasad S. Goudar, M.D., Richard Derman, M.D., M.P.H., Adrien Lokangaka, M.D., M.P.H., Antoinette Tshefu, M.D., Ph.D., M.P.H., Melissa Bauserman, M.D., M.P.H., Carl Bose, M.D., Poonam Shivkumar, M.D., Manju Waikar, M.D., Archana Patel, M.D., Ph.D., Patricia L. Hibberd, M.D., Ph.D., Paul Nyongesa, M.D., Fabian Esamai, M.B., Ch.B., M.P.H., Ph.D., Osayame A. Ekhaguere, M.B., B.S., M.P.H., Sherri Bucher, Ph.D., Saleem Jessani, M.B., B.S., Shiyam S. Tikmani, M.B., B.S., Sarah Saleem, M.B., B.S., Robert L. Goldenberg, M.D., Sk M. Billah, M.P.H., Ruth Lennox, M.B., Ch.B., Rashidul Haque, M.D., William Petri, M.D., Lester Figueroa, M.D., Manolo Mazariegos, M.D., M.P.H., Nancy F. Krebs, M.D., Janet L. Moore, M.S., Tracy L. Nolen, D.Ph. and Marion Koso-Thomas, M.D., M.P.H. for the A-PLUS Trial Group, 9 February 2023, New England Journal of Medicine.
DOI: 10.1056/NEJMoa2212111

The research was supported by The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the Foundation for the National Institutes of Health through the Maternal, Newborn & Child Health Discovery & Tools initiative of the Bill and Melinda Gates Foundation.

Antibiotic Breakthrough: The Power of a Plant-Derived Toxin

A powerful plant-derived toxin with a unique way of killing harmful bacteria has been identified as one of the most promising new antibiotics in decades.

Albicidin, a new antibiotic, is produced by the plant pathogen Xanthomonas albilineans, responsible for causing sugar cane’s destructive leaf scald disease. The toxin is believed to aid the pathogen’s spread by attacking the plant. Albicidin has been shown to be highly effective against harmful bacteria, including drug-resistant superbugs such as E. coli and S. aureus.

Despite its antibiotic potential and low toxicity in pre-clinical experiments, pharmaceutical development of albicidin has been hampered because scientists did not know precisely how it interacted with its target, the bacterial enzyme DNA gyrase (gyrase). This enzyme binds to DNA and, through a series of elegant movements, twists it up, a process known as supercoiling which is vital for cells to function properly.

Now, Dr. Dmitry Ghilarov’s research group at the John Innes Centre, alongside the laboratories of Prof. Roderich Süssmuth at Technische Universität Berlin, Germany, and Prof. Jonathan Heddle at Jagiellonian University, Poland, have exploited advances in cryo-electron microscopy to obtain a first snapshot of albicidin bound to gyrase.

It showed that albicidin forms an L-shape, enabling it to interact with both the gyrase and the DNA in a unique way. In this state, gyrase can no longer move to bring the DNA ends together. The effect of albicidin is akin to a spanner thrown between two gears.

The way albicidin interacts with gyrase is sufficiently different from existing antibiotics that the molecule and its derivatives are likely to be effective against many of the current antibiotic-resistant bacteria.

“It seems by the nature of the interaction, albicidin targets a really essential part of the enzyme and it’s hard for bacteria to evolve resistance to that,” said Dr. Ghilarov. “Now that we have a structural understanding, we can look to further exploit this binding pocket and make more modifications to albicidin to improve its efficacy and pharmacological properties.”

This work has already begun: the team used their observations to chemically synthesize variations of the antibiotic with improved properties. In tests, these variants were effective against some of the most dangerous hospital-acquired bacterial infections including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella typhimurium.

Dr. Ghilarov said: “We believe this is one of the most exciting new antibiotic candidates in many years. It has extremely high effectiveness in small concentrations and is highly potent against pathogenic bacteria – even those resistant to the widely used antibiotics such as fluoroquinolones.”

“This molecule has been around for decades”, continued Dr. Ghilarov, “Now advances in cryo-electron microscopy has made it possible to determine structures of even the most elaborate protein-DNA complexes. To be the first person to see the molecule bound to its target and how it works is a huge privilege, and the best reward one can have as a scientist. But this work is a big team effort, and we would not have done it without our European colleagues.”

The next step for this research is to engage with academic and industrial collaborators and to seek funding to take the research forward to human clinical trials. This could lead to the development of an urgently needed new class of antibiotics in the face of a global threat of antimicrobial resistance, AMR.

Albicidin targets an enzyme found in both plants and bacteria called DNA gyrase (or simply “gyrase”). This enzyme binds to DNA and, through a series of elegant movements, twists it up (a process known as supercoiling) – a vital process for cells to function properly. However, gyrase has an Achilles heel; to do its job it must momentarily cut the DNA double helix. This is dangerous, as broken DNA is lethal to the cell. Normally, gyrase quickly joints the two pieces of DNA back together again as it works, but albicidin prevents it from happening, resulting in broken DNA and bacterial death. 

Multi-drug resistant pathogens such as Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhimurium present a dangerous healthcare burden, exacerbated by the COVID-19 pandemic. 

Infections by resistant pathogens are a leading cause of death in hospital intensive care units, with some strains becoming pan-resistant. Gram-negative drug-resistant pathogens were a cause of 50,000 deaths in 2019. 

Despite urgently needed new medicines to combat this threat, drug discovery programs have yielded no new classes of antibiotics for several decades. 

Reference: “Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin” by Elizabeth Michalczyk, Kay Hommernick, Iraj Behroz, Marcel Kulike, Zuzanna Pakosz-Stępień, Lukasz Mazurek, Maria Seidel, Maria Kunert, Karine Santos, Holger von Moeller, Bernhard Loll, John B. Weston, Andi Mainz, Jonathan G. Heddle, Roderich D. Süssmuth and Dmitry Ghilarov, 23 January 2023, Nature Catalysis.
DOI: 10.1038/s41929-022-00904-1