Tag Archives: Bacteriology

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

Infections with many different types of bacteria including Streptococcus pneumonia, Listeria monocytogens, and Neisseria mengitidis can cause bacterial …

Infections with many different types of bacteria including Streptococcus pneumonia, Listeria monocytogens, and Neisseria mengitidis can cause bacterial meningitis. It’s estimated that every year over 1.2 million cases of bacterial meningitis happen around the world, and without treatment, this deadly disease is fatal to seven of ten people who are sickened by it. Even with antibiotic treatments, three of ten patients die. Survivors are left with issues like chronic headaches, seizures, loss of vision or hearing, and other neurological consequences. New research reported in Nature has revealed how bacteria are able to penetrate the meninges that surround and protect the brain to cause bacterial meningitis. The findings have shown that bacteria use neurons to evade immunity and infect the brain, and the work may aid in the creation of new therapeutics.

A digitally-colorized SEM image depicts of Streptococcus pneumoniae bacteria (lavender), as they were being attacked by a white blood cell (pink).  / Credit: CDC/ Dr. Richard Facklam

Right now, antibiotics can help eliminate the bacterial pathogens that cause this illness. But steroids are also needed to control the dangerous inflammation that can occur along with the infection. However, reducing inflammation also weakens the immune response, making it harder to get rid of the infection.

In this research, the scientists used Streptococcus pneumoniae and Streptococcus agalactiae bacteria, which can both cause bacterial meningitis in humans. They determined that when these bacteria get to the meninges, they release a toxin, which activates neurons in the meninges that sense pain. This pain neuron activation could explain why bacterial meningitis patients get horrible headaches, noted the researchers.

The activated pain neurons then release a signaling molecule called CGRP, which binds to a receptor called RAMP1 on the surface of immune cells called macrophages. Once CGRP binds to RAMP1 on macrophages, the immune cells are basically disabled, and they stop responding to bacterial infections like they normally would.

The link between CGRP and RAMP1 on macrophages also stops them from signaling to other immune cells, which allows the bacterial infection to not only penetrate the meninges but to spread infection.

This work was confirmed with the use of a mouse model that lacked the pain neurons that are activated by bacteria. Compared to mice with those neurons, the engineered mice had less severe brain infections when they were exposed to bacteria that cause meningitis. There were also lower levels of CGRP in the engineered mice compared to normal mice. The normal mice, however, had higher levels of bacteria in the meninges.

Additional experiments also showed that when mice were treated with drugs that block RAMP1, the severity of the bacterial infection was reduced. Mice treated with RAMP1 blockers were able to clear their infections faster too.

It may be possible to help the immune system clear cases of bacterial meningitis with medications that block either CGRP or RAMP1, potentially in conjunction with antibiotics. There are already drugs that can do this, and they are generally used to treat migraine.

Sources: Harvard Medical School, Nature

Carmen Leitch

Rheumatoid arthritis (RA)  is a complex, chronic inflammatory disease that is thought to affect about one percent of …

Rheumatoid arthritis (RA)  is a complex, chronic inflammatory disease that is thought to affect about one percent of the world’s population. RA happens when a person’s own antibodies attack joint tissue, causing painful swelling, stiffness, and redness. Some research has suggested that there is a link between RA and gum disease.

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Gum disease is estimated to affect up to 47 percent of adults, and in the disorder, oral microbes can move to the blood after the gums start to bleed. An increase in disease activity has been observed in RA patients who also have gum disease. Gum disease has been shown to be more common in RA patients who carry a certain type of antibodies, called anti-citrullinated protein antibodies (ACPAs), though ACPAs are often found in the blood of individuals with RA. The presence of ACPAs can often predate the diagnosis of RA by a few years.

A new study investigated the connections between these observations. In this work, the researchers collected blood samples from a small group of ten people with RA, five with and five without gum disease. These samples were collected every week for one year, and the investigators assessed the expression of both human and bacterial genes in those samples.

Certain types of inflammatory immune cells carried gene expression signatures that were associated with the autoimmune flares of arthritis patients who also had periodontal disease, as well as the presence of certain oral bacteria in the blood.

Many of these oral bacteria were chemically altered by deimination; they were citrullinated. Citrullination can change the structure and function of proteins. Although citrullination can be a part of the normal function of tissues, high levels of citrullination have been linked to inflammation.

Citrullination can also create targets for ACPAs; when the normal, unconverted forms of the oral bacteria were incubated with ACPAs, the antibodies did not react, but when the citrullinated oral bacteria were exposed to ACPAs, there was a reaction. ACPAs appear to be bound to oral microbes in RA patients.

The findings have been reported in Science Translational Medicine.

The study noted that the immune response to oral microbes could be influencing RA flares, that oral microbes can trigger a specific antibody reaction in patients with both RA and gum disease, and that RA flares cause varying immune signatures, which could reflect different flare triggers.

It could be that gum disease repeatedly causes the immune system to respond, and as the immune system keeps reacting and repeatedly increasing inflammation, RA may eventually begin to emerge. More work will be needed, however, to fully understand whether gum disease is playing a causative role in the development of RA.

Source: Science Translational Medicine

Carmen Leitch

Scientists have found that a gene that has been previously identified in many animals and their associated microbes …

Scientists have found that a gene that has been previously identified in many animals and their associated microbes can enable resistance to antimicrobial drugs. The resistance gene encodes for an enzyme called EstT, which can deactivate antibiotic drugs known as macrolides. The enzyme can disrupt the chemical ring structure of these antibiotics through hydrolysis. When the ring is broken or opened with water, the antibiotic loses both its active shape, and its target affinity, explained study leader Dr. Tony Ruzzini PhD, an assistant professor at the Western College of Veterinary Medicine (WCVM) of the University of Saskatchewan. The findings have been reported in the Proceedings of the National Academy of Sciences.

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This gene can take macrolide antibiotics out of commission, and illnesses can no longer be treated effectively. Macrolides such as tylosin, tilmicosin and tildipirosin are often used to treat cattle with bovine respiratory disease or liver abscesses, and may also be used to treat other diseases in livestock and companion animals.

In this study, the researchers analyzed genes that were found within microbes that were living in watering bowls at a beef cattle feedlot in western Canada. The investigators isolated the microbes that were in the water, and compared the genes in the microbes to databases of antimicrobial resistance genes.

A bacterium called Sphingobacterium faecium WB1 was found to carry the EstT gene, which was contained within a cluster of three antibiotic resistance genes (ARGs). It was also near plasmids and retrotransposons, suggesting it can move easily from one microbe to another. EstT is commonly found in microbes in the human microbiome too.

“This gene, even though we found it in an environmental organism, it is also present in pathogens that are responsible for causing bovine respiratory disease,” noted Ruzzini.

“Our finding adds to the considerable database of ARGs, which can be crossmatched to a bacteria’s DNA to determine if the bacterium has the potential to be resistant to a particular antimicrobial,” said first study author Dr. Poonam Dhindwal PhD, a postdoctoral fellow at WCVM.

The researchers are continuing to study EstT to learn more about how it works.

“As [antimicrobial resistance] surveillance systems rely more on molecular tools for detection, our knowledge of this specific gene and its integration into those systems will help to better inform antimicrobial use,” said Ruzzini.

Sources: University of Saskatchewan, Proceedings of the National Academy of Sciences (PNAS)

Carmen Leitch

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

Mycobacterial biotin biosynthesis counters airway alkalinity

Daher, W., Kremer, L. Mycobacterial biotin biosynthesis counters airway alkalinity.
Nat Microbiol (2023). https://doi.org/10.1038/s41564-023-01330-0

Even though humans are complex organisms and bacteria are single cells, and each are made of completely different …

Even though humans are complex organisms and bacteria are single cells, and each are made of completely different cell types (eukaryotic and prokaryotic cells, respectively), there are some similar immune mechanisms at work in both of them. Scientists have now learned more about how a complex found in both human and bacterial cells, a group of enzymes called ubiquitin transferases, works to regulate immune pathways. The findings, which have been reported in Nature, may provide new insights into treatments for a wide range of human diseases, suggested the researchers.

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“This study demonstrates that we’re not all that different from bacteria,” said senior study author Aaron Whiteley, an assistant professor at the University of Colorado Boulder. “We can learn a lot about how the human body works by studying these bacterial processes.”

Some research has suggested that the immune system found in humans has its origins in bacterial cells. Bacteria have to fight their own infections from other microbes like bacteriophages, viruses that infect bacterial cells. The CRISPR gene editing tool is derived from a bacterial immune defense.

An enzyme called cGAS (cyclic GMP-AMP synthase) can be found in humans, and a simpler version of it is also carried by bacteria; cGAS works to activate an immune defense when viral pathogens are detected.

Researchers have now analyzed the structure of bacterial cGAS, and revealed other proteins that are involved in the response to a viral infection. This study has shown that in bacteria, cGAS is modified by a simplified form of ubiquitin transferase, a crucial enzyme also found in human cells.

Bacteria are far easier to manipulate genetically compared to human cells, so this opens up a world of new research opportunities, said co-first study author Hannah Ledvina, PhD, a postdoctoral researcher. “The ubiquitin transferases in bacteria are a missing link in our understanding of the evolutionary history of these proteins.”

In this research, the scientists have also revealed two critical parts of ubiquitin transferase: Cap2 and Cap3 (CD-NTase-associated protein 2 and 3) that activate and deactivate the cGAS response, respectively.

In humans cells, ubiquitin tags also work to mark cellular garbage, like dysfunctional or unnecessary proteins that have to be degraded and disposed. Problems with this system can lead to a buildup of cellular trash, which may lead to some disorders, such as neurodegeneration.

Thus, while more research is needed, the study authors are hopeful that this work will enable us to learn more about many diseases, including autoimmune disorders like arthritis or neurodegenerative diseases such as Parkinson’s disease

Parts of the bacterial ubiquitin transferase complex, like Cap3 – the off switch, could be harnessed to eliminate some pathologies related to human disease, suggested Whiteley.

Sources: University of Colorado at Boulder, Nature

Carmen Leitch

The microbes of the world battle one another for domination, and some bacteria produce powerful molecules that can …

The microbes of the world battle one another for domination, and some bacteria produce powerful molecules that can work against other microbes. Researchers have now discovered that some Pseudomonas bacteria generate strong antimicrobials that work against pathogenic fungi that affect humans, as well as plant fungal diseases. The findings have been reported in the Journal of the American Chemical Society.

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The chemicals that have been identified are called keanumycins, and these compounds can destroy a plant pest called Botrytis cinerea, which causes grey mold rot and leads to huge economic losses annually. Keanumycins can also inhibit pathogenic fungi that affect humans, including Candida albicans. Previous studies have indicated that it’s harmless to human and plant cells.

Keanumycins may offer an environmentally friendly way to protect plants without using chemical pesticides. They may also be a weapon in the battle against drug-resistant fungi.

“We have a crisis in anti-infectives,” noted first study author Sebastian Götze, a postdoc at Leibniz-HKI. “Many human pathogenic fungi are now resistant to antimycotics, partly because they are used in large quantities in agricultural fields.”

The research team has been investigating Pseudomonas bacteria for a long time, and they know that many types of Pseudomonas are toxic to amoeba. The deadly effect of the bacteria is due to a few compounds that the investigators have traced to the Pseudomonas genome. The natural products are lipopeptides called keanumycins A, B and C, which have soap-like characteristics.

One of those keanumycins was isolated so it could be studied further. “The lipopeptides kill so efficiently that we named them after Keanu Reeves because he, too, is extremely deadly in his roles,” quipped Götze.

Some fungi have a resemblance to amoeba, and the researchers suspected keanumycins would also kill fungi. Indeed, tests reveled that Keanumycin could kill grey mould rot on hydrangea leaves. With only the fluid collected from a culture of bacterial, fungal growth slowed.

Additional work will be needed to confirm the findings, but the liquid from Pseudomonas cultures could be used on plants, Götze noted.

Keanumycin is also biodegradable, which suggests that permanent residues from the compound won’t contaminate soil, and it could be an environmentally friendly pesticide alternative.

“In addition, we tested the isolated substance against various fungi that infect humans. We found that it strongly inhibits the pathogenic fungus Candida albicans, among others,” added Götze. There aren’t many antifungals on the market, so this would be a welcome addition to the pharmacy.

Sources: Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute, Journal of the American Chemical Society

Carmen Leitch

Gut feelings can be very real. There are neurons that connect the gut directly to the brain, and …

Gut feelings can be very real. There are neurons that connect the gut directly to the brain, and this so-called gut-brain axis has a significant influence on the body.
The microbes in the gut can also affect the brain, and researchers are trying to decipher the complex relationship between the brain and microorganisms in the body. Recent work has shown how microbial metabolites can influence brain function. Neurotransmitters can also affect gut physiology. Now scientists have developed a process that can be used by other researchers to develop a deep understanding of how gut microbes impact the brain. The work has been reported in Nature Protocols.

Image credit: Pixabay

“Currently, it is difficult to determine which microbial species drive specific brain alterations in a living organism,” said first study author, Dr. Thomas D. Horvath, an instructor at Baylor College of Medicine and Texas Children’s Hospital. “Here we present a valuable tool that enables investigations into connections between gut microbes and the brain.”

“Gut microbes can communicate with the brain through several routes, for example by producing metabolites, such as short-chain fatty acids and peptidoglycans; neurotransmitters, such as gamma-aminobutyric acid and histamine; and compounds that modulate the immune system as well as others,” added co-first study author Dr. Melinda A. Engevik, an assistant professor at the Medical University of South Carolina.

Related: Bugs on the Brain – Gut Microbes Affect Neurodegeneration

In this process, the researchers suggest creating a three-stage workflow. First, microbes should be prepared in a defined culture media. Next, intestinal organoids are injected with the microbes.  Finally, animal models are used that have either complete gut microbiomes; germ-free mice that lack microbiomes; mice that began as germ-free but were colonized with gut microbiota that carried no pathogens; and mice that started out germ-free but were colonized with individual strains of a gut microbe – Bifidobacterium dentium or Bacteroides ovatus.

The short-chain fatty acids produced by gut microbes can have a physiological impact on the brain, and they can be isolated and analyzed by  liquid chromatography–tandem mass spectrometry (LC/MS) along with any neurotransmitters that are derived from microbes.

This methodology is different from research that only assesses material in stool samples, because it encompasses many other things including in vivo models and cell cultures. The study authors estimated that the mouse colonization process requires about three weeks and LC/MS techniques take about another two weeks.

“We can expand our study to a community of microbes,” said study co-author Dr. Jennifer K. Spinler, an assistant professor at Baylor and the Texas Children’s Hospital Microbiome Center. “This protocol gives researchers a road map to understand the complex traffic system between the gut and the brain and its effects.”

Sources: Baylor College of Medicine, Nature Protocols

Carmen Leitch

The human gut microbiome exerts a significant influence on many aspects of our physiology. While it may not …

The human gut microbiome exerts a significant influence on many aspects of our physiology. While it may not be surprising that gut microbes can affect gut health, studies have also suggested that the gut microbiome can play a role in neurodegenerative diseases. What is less clear is whether those brain diseases are changing the microbes in the gut, or if gut microbes influence the health of the brain. New research has suggested that gut microbes generate molecules, such as short-chain fatty acids, that can exacerbate neurodegenerative conditions. The findings have been reported in Science.

Image credit: Pixabay

“We gave young mice antibiotics for just a week, and we saw a permanent change in their gut microbiomes, their immune responses, and how much neurodegeneration related to a protein called tau they experienced with age,” said senior study author David M. Holtzman, MD, a Professor at Washington University School of Medicine in St. Louis. “What’s exciting is that manipulating the gut microbiome could be a way to have an effect on the brain without putting anything directly into the brain.”

In this work, the researchers used a mouse model in which the animal are predisposed to brain damage that causes cognitive impairment. These mice express a mutated form of a protein called tau in the brain; tau tangles have been linked to neurodegenerative diseases including Alzheimer’s and Parkinson’s. In these mice, the mutant tau protein accumulates, as in disease, and causes the neurons of the brain to atrophy before the mice are 40 weeks old. These mice also carried a human APOE gene variant, APOE4, which is known to significantly increase the risk of Alzheimer’s.

When the researchers also ensured that these mice did not develop gut microbiomes by raising the germ-free mice in sterile conditions from birth, their brains acquired far less damage by 40 weeks compared to the same mice that were raised to have normal gut microbiomes.

If the mouse model with a microbiome was also given antibiotics when they were two weeks old, the composition of the bacterial species in their microbiomes was permanently altered. In male mice, this antibiotic-induced microbiome change was accompanied by a reduction in the brain damage that is typically seen at 40 weeks in these mice. Male mice that did not carry APOE4 also had more neuroprotection, potentially because the APOE4 variant may render some of the protection ineffective, suggested the researchers. Antibiotics did not affect neurodenegeration in female mice.

While researchers know that immune cells in male and female brains don’t respond to stimuli in the same way, the researchers don’t yet know what these findings mean for patients with neurodegeneration, noted Holtzman.

Additional work revealed that three specific short-chain fatty acids, generated by metabolic processes in some gut bacteria, are linked to neurodegeneration. There were only low levels of these fatty acids in mice with antibiotic-exposed gut microbiomes, and they were undetectable in mice lacking gut microbiomes – the mice with less brain damage.

The short-chain fatty acids may be triggering neurodegeneration by activating immune cells in circulation, which leads to immune cells in the brain to harm brain tissue. When mice lacking microbiomes consumed the three short-chain fatty acids, immune cells in the mouse brains became more reactive, and there were more signs of brain damage linked to tau.

The researchers are exploring whether modifications to the gut microbiome are a way to treat neurodegeneration.

In an unrelated study, scientists have also developed a new method for assessing interactions between the microbiome and the brain, which will help reveal more about this complex relationship and its health consequences.

Sources: Washington University School of Medicine, Science

Carmen Leitch