Carbon Chemist

Tag: Antibiotic

  • IPIAD augments standard therapy for pancreatic ductal adenocarcinoma

    IPIAD augments standard therapy for pancreatic ductal adenocarcinoma

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    A new research perspective was published in Oncoscience (Volume 11) on February 7, 2024, entitled, “IPIAD- an augmentation regimen added to standard treatment of pancreatic ductal adenocarcinoma using already-marketed repurposed drugs irbesartan, pyrimethamine, itraconazole, azithromycin, and dapsone.”

    In this new paper, researcher Richard E. Kast from IIAIGC Study Center presents the data and rationale for adding five generic non-oncology drugs from general medical practice to gemcitabine, nab-paclitaxel, a current standard cytotoxic chemotherapy of pancreatic ductal adenocarcinoma. The regimen, called IPIAD, uses an angiotensin receptor blocker (ARB) irbesartan indicated for treating hypertension, an old antimicrobial drug pyrimethamine indicated for treating toxoplasmosis or malaria, an old antifungal drug itraconazole, an old broad spectrum antibiotic azithromycin, and an old antibiotic dapsone. 

    “In reviewing selected growth driving systems active in pancreatic ductal adenocarcinoma then comparing these with detailed data on ancillary attributes of the IPIAD drugs, one can predict clinical benefit and slowing growth of pancreatic ductal adenocarcinoma by this augmentation regimen.”

    Source:

    Journal reference:

    Kast, R. E. (2024). IPIAD- an augmentation regimen added to standard treatment of pancreatic ductal adenocarcinoma using already-marketed repurposed drugs irbesartan, pyrimethamine, itraconazole, azithromycin, and dapsone. Oncoscience. doi.org/10.18632/oncoscience.594.

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  • A global threat to human, animal, and plant health

    A global threat to human, animal, and plant health

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    Fungi can cause disease in both humans, animals, and plants. Every year, 1.5 million people die from fungal infections, and fungal attacks in food crops threaten food production. To protect ourselves, we have developed chemical agents – in the form of medicines or pesticides – that kill harmful fungi. The most effective remedy against fungal infections is a group of substances collectively known as azoles.

    It is vital that the azoles we use against pathogenic fungi have a good effect.”


    Ida Skaar, senior researcher, Norwegian Veterinary Institute

    Azoles are indeed frequently used – as medicine for humans and animals, to prevent fungal diseases in food crops and on golf courses, to preserve wood, to prevent mould in flower bulbs and silage, and to preserve ornamental plants. The list is long. This frequent use causes researchers to worry because the harmful fungus develops resistance.

    A little-explored topic

    Antibiotic resistance is a well-known issue that raises concern among many. In comparison, fungicide resistance is a little-explored, but very relevant, topic. The World Health Organization (WHO) has, among other organisms, singled out the fungus Aspergillus fumigatus as a fungus that can pose a health threat in the future. A. fumigatus is a common fungus found everywhere, and it poses little threat to healthy people. For people with a compromised immune system, it can cause infections that need to be treated. In such cases it is vital that the medicine, which is usually based on azoles, is effective.

    “A. fumigatus that is resistant to azoles is an increasing global problem,” Skaar says.

    “We do not know how the situation in Norway is, but with the wetter and warmer climate that we can probably expect in the future, the problem will become greater.

    “Knowledge about the situation in Norway is absolutely necessary. We must be proactive and have the necessary knowledge before the problem becomes too serious. We must, among other things, know how much resistance we have, in what way the fungus develops resistance, and in which environments resistance is likely to arise (so-called hotspots).

    One Health – everything is connected

    Skaar leads the project NavAzole which aims to map and understand the development of azole resistance in Norway. This knowledge is needed to make wise decisions to keep the resistance level as low as possible. This requires cooperation between different sectors.

    “Azole resistance concerns several sectors. We must therefore keep the One Health perspective in mind when working with it. This means that we must acknowledge the important connection between human health, animal health, and the surrounding environment. We need to consider all the application areas of azoles, and investigate hotspots for resistance development, and how resistance is spread further,” the senior researcher elaborates.

    Looking for resistance in soil dwelling fungi

    A potential hotspot for resistance development is the use of azole-based pesticides in agriculture. In the project, NIBIO will work with this issue.

    Andrea Ficke is a researcher from NIBIO, working with fungal diseases in cereals. She explains how a cereal field can be a hotspot for resistance development:

    “A. fumigatus is a soil dwelling fungus that also exists in the field. In conventional agriculture, the crops are sprayed against various fungal diseases, and many of the fungicides are based on azoles. Some of the fungicides will end up in the soil and can affect A. fumigatus. In the same way that a high use of antibiotics can lead to bacteria developing resistance, regular exposure to azoles can lead to resistance in A. fumigatus. “

    In the project, the researchers therefore want to investigate whether they find resistant A. fumigatus in cereal fields that are sprayed with azole-based fungicides, and whether there is a correlation between resistance development in plant pathogenic fungi and resistance development in A. fumigatus.

    “We are going to study two fungi that cause the leaf blotch diseases septoria leaf blotch (Zymoseptoria tritici) and septoria nodorum blotch (Parastagonospora nodorum). These diseases can lead to a considerable loss of crops,” Ficke explains.

    Ficke has been working on leaf blotch diseases in cereals for 10-12 years. During these years, she has not observed a worrying increase in resistance to fungicides. So far, Skaar’s research group has also not found resistant A. fumigatus in fields. However, this does not mean that we can rest on our laurels, quite the contrary.

    Preventive work is important

    “In Norway, we are very fortunate not to have major problems with fungicide resistance in crops,” Ficke says.

    Although Skaar has found more resistant A. fumigatus in various Norwegian environments than expected, she also believes that the problem is relatively small in Norway. “But you don’t have to go further than to Denmark before the situation is more serious, ” she adds.

    Both researchers emphasize the importance of focusing on this issue in Norway.

    “The preventive efforts we put in are crucial. We must understand the extent of the problem in Norway, and we must implement measures that can reduce the development of resistance. The use of integrated pest management plays an important role in this, by reducing unnecessary use of fungicides. In addition, one should consider in which situations it is necessary to use fungicides. “

    “Norway excels at avoiding unnecessary use of antibiotics, and we should focus equally on avoiding unnecessary use of fungicides. When resistance becomes properly established, it is very difficult to eradicate. Therefore, we must be proactive,” the researchers conclude.

    How do fungi develop resistance?

    In all fungal populations, there exists a certain genetic variation. This variation can make some “individuals” more tolerant to the exposure to fungicides than others. When the population is exposed to fungicides, these “individuals” will survive, and can reproduce. The resistance to fungicides is genetic, and thus hereditary. Random mutations can also occur in the DNA of the fungus, making it resistant. In this way, the use of the same type of fungicide over a long time will select for fungi that are increasingly resistant. The faster the fungi reproduce the faster resistance can occur.

    Different fungicides have different strategies to kill or inhibit fungi. An “individual” that has developed resistance to one type of fungicide is not necessarily resistant to a fungicide that works in a different way. Therefore, it is important to avoid one-sided use of fungicides with the same mode of action. In addition, in plant production, one should use integrated pest management (IPM) to reduce the need for fungicides (and other pesticides).

    Source:

    NIBIO – Norwegian Institute of Bioeconomy Research

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  • Hormonal steroids could make gonorrhea untreatable

    Hormonal steroids could make gonorrhea untreatable

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    You know that package warning that oral birth control won’t prevent STIs? Well in the case of gonorrhea, the sexually transmitted bacterium that causes the disease can use those hormones to help it resist antibiotic attacks.

    Like many bacteria, this bug, Neisseria gonorrhoeae, is equipped with pumps to push the killing chemicals out of its cells. But what’s unique, according to a Duke and Emory study online this week in Nature Communications, is that the hormones of the human urogenital tract actually allow gonorrhea to make and use more of these pumps to fight intrinsic antimicrobials and prescribed antibiotics.

    The researchers uncovered the trick while examining a transcription factor – a protein that binds to specific sites on the bacterium’s DNA and slows production of the efflux pumps that protect it.

    Led by Duke graduate student Grace Hooks and her mentor, Biochemistry chair Richard Brennan, Ph.D., the study used a variety of approaches to characterize the shape and function of the transcription factor.

    What they found is that, unfortunately, this transcription factor, called MtrR, has an affinity for binding to the hormonal steroids progesterone, estrogen and testosterone and the synthetic hormone ethinyl estradiol. When it binds to a hormone, the transcription factor becomes less effective at suppressing the production of bacterial pumps.

    Hooks said the bacterium appears to be able to sense its hormonal environment and waits for the opportune time in the female’s menstrual cycle to ramp up its colonization.

    Estrogen rises dramatically in the week before ovulation, and progesterone peaks in the two weeks between ovulation and menstruation. These fluctuations are thought to suppress the immune system, giving sperm and eggs a window of opportunity to survive in the urogenital tract, but that same window also creates a vulnerability to this infection.

    It’s kind of utilizing this sensory system to gauge where it is in this cycle and when it can best colonize. It can only survive in the human host, it can’t survive outside. So, it has to really be good at sensing where it is and when’s the best time for colonizing.”


    Grace Hooks, Duke graduate student 

    The transcription factor MtrR also helps signal the bacterium to protect itself against reactive oxygen species. “What this one protein does is a dual system to protect Neisseria gonorrhea,” Brennan said.

    Gonorrhea has been with humans far longer than there have been antibiotics, appearing in texts as ancient as 2600 BC and making famous appearances in Julius Caesar’s Roman legions and the Crimean war.

    Ancient or not, the Centers for Disease Control considers gonorrhea an urgent public health threat, because it is now resistant to every antibiotic except for one, ceftriaxone. But strains resistant to this antibiotic have been identified recently in Europe and Asia.

    Known historically and colloquially as ‘the clap,’ untreated gonorrhea in women can lead to pelvic inflammatory disease and infertility. It may also be passed from mother to infant during childbirth.

    While the infection is more obvious in men, it is less dramatic, as men don’t experience the wider hormonal shifts, nor is their urogenital tract as complicated or deep as a woman’s, Hooks said. But men still carry all the same hormones that the transcription factor latches onto, she added.

    And, of course, the bacteria must thrive in both men and women to be a successful STI. “Neisseria gonorrhoeae is an obligate human pathogen,” Brennan said. “We don’t know where it is the rest of the time.”

    When Hooks presented some of her data in a laboratory meeting, fellow graduate student Emily Cannistraci from the next-door Schumacher laboratory asked if the synthetic hormone ethinyl estradiol, which is found in many oral contraceptives for women, would have a similar effect. Hooks checked, and it certainly did.

    The takeaway is not only the package warning that oral birth control won’t prevent STIs, but in this case, it might even make them worse.

    This research was supported by the National Institutes of Health (R35GM130290, R05 AI048593, R01 AI021150), the US Department of Veterans Affairs and the U.S. Department of Energy.

    Source:

    Journal reference:

    Hooks, G. M., et al. (2024). Hormonal steroids induce multidrug resistance and stress response genes in Neisseria gonorrhoeae by binding to MtrR. Nature Communications. doi.org/10.1038/s41467-024-45195-1

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  • Researchers identify a new approach to controlling bacterial infections

    Researchers identify a new approach to controlling bacterial infections

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    Researchers at the Icahn School of Medicine at Mount Sinai have identified a new approach to controlling bacterial infections. The findings were described in the February 6 online issue of Nature Structural & Molecular Biology [DOI # 10.1038/s41594-024-01220-x].

    The team found a way to turn on a vital bacterial defense mechanism to fight and manage bacterial infections. The defense system, called cyclic oligonucleotide-based antiphage signaling system (CBASS), is a natural mechanism used by certain bacteria to protect themselves from viral attacks. Bacteria self-destruct as a means to prevent the spread of virus to other bacterial cells in the population.

    We wanted to see how the bacterial self-killing CBASS system is activated and whether it can be leveraged to limit bacterial infections. This is a fresh approach to tackling bacterial infections, a significant concern in hospitals and other settings. It’s essential to find new tools for fighting antibiotic resistance. In the war against superbugs, we need to constantly innovate and expand our toolkit to stay ahead of evolving drug resistance.”


    Aneel Aggarwal, PhD, Co-Senior Author, Professor of Pharmacological Sciences at Icahn Mount Sinai

    According to a 2019 report by the Centers for Disease Control and Prevention, more than 2.8 million antimicrobial-resistant infections occur in the United States each year, with over 35,000 people dying as a result.

    As part of the experiments, the researchers studied how “Cap5,” or CBASS-associated protein 5, is activated for DNA degradation and how it could be used to control bacterial infections through a combination of structural analysis and various biophysical, biochemical, and cellular assays. Cap5 is a key protein that becomes activated by cyclic nucleotides (small signaling molecules) to destroy the bacterial cell’s own DNA.

    “In our study, we started by identifying which of the many cyclic nucleotides could activate the effector Cap5 of the CBASS system,” says co-senior author Olga Rechkoblit, PhD, Assistant Professor of Pharmacological Sciences at Icahn Mount Sinai. “Once we figured that out, we looked closely at the structure of Cap5 when it’s bound to these small signaling molecules. Then, with expert help from Daniela Sciaky, PhD, a researcher at Icahn Mount Sinai, we showed that by adding these special molecules to the bacteria’s environment, these molecules could potentially be used to eliminate the bacteria.”

    The researchers found that determining the structure of Cap5 with cyclic nucleotides posed a technical challenge, requiring expert help from Dale F. Kreitler, PhD, AMX Beamline Scientist at Brookhaven National Laboratory. It was achieved by using micro-focused synchrotron X-ray radiation at the same facility. Micro-focused synchrotron X-ray radiation is a type of X-ray radiation that is not only produced using a specific type of particle accelerator (synchrotron) but is also carefully concentrated or focused on a tiny area for more detailed imaging or analysis.

    Next, the researchers will explore how their discoveries apply to other types of bacteria and assess whether their method can be used to manage infections caused by various harmful bacteria.

    The paper is titled “Activation of CBASS-Cap5 endonuclease immune effector by cyclic nucleotides.”

    Other authors who contributed to this work are Angeliki Buku, PhD, and Jithesh Kottur, PhD, both with Icahn Mount Sinai.

    The work was funded by National Institutes of Health grants R35-GM131780, P41GM111244, KP1605010, P30 GM124165, S10OD021527, GM103310, and by the Simons Foundation grant SF349247.

    Source:

    Mount Sinai Health System

    Journal reference:

    Rechkoblit, O., et al. (2024). Activation of CBASS Cap5 endonuclease immune effector by cyclic nucleotides. Nature Structural & Molecular Biology. doi.org/10.1038/s41594-024-01220-x.

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  • Does your diet increase the risk of recurring urinary tract infections?

    Does your diet increase the risk of recurring urinary tract infections?

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    In a recent study published in JAMA Network Open, a group of researchers assessed the influence of behavioral risk factors such as diet, body weight, and lifestyle on the prevalence of urinary infections.

    Study: Incidence of Urinary Infections and Behavioral Risk Factors. Image Credit: valiantsin suprunovich/Shutterstock.comStudy: Incidence of Urinary Infections and Behavioral Risk Factors. Image Credit: valiantsin suprunovich/Shutterstock.com

    Background 

    Urinary infections, increasingly prevalent with over 404.6 million cases globally in 2019, significantly impact life quality and can lead to premature death if not managed well.

    Risk factors commonly caused by bacteria like Escherichia coli include age, sexual behavior, female anatomy, immune suppression, and contraceptive methods. Antibiotic misuse exacerbates pathogen resistance, complicating treatment.

    Untreated urinary tract infections (UTIs) can cause severe complications like pyelonephritis, renal failure, and risks during pregnancy. Recurrences are common and are influenced by various lifestyle and health factors.

    Diet and lifestyle play crucial roles in prevention, with proper nutrition, hydration, and healthy habits essential in reducing recurrence risks and improving immune resistance.

    Further research is necessary to understand better and effectively address the complex interplay of factors influencing the incidence and recurrence of urinary infections.

    About the study 

    The present study, adopting a cross-sectional observational design, utilized a 39-item questionnaire to explore the frequency of urinary infections in relation to behavioral risk factors. Literature, expert opinions, and the target population’s characteristics informed the questionnaire’s development.

    Distributed online between July and August 2023 through social media, WhatsApp, and institutional emails, the survey targeted employees and students across three Romanian university centers.

    An emphasis was placed on anonymity and data protection to ensure participant confidentiality and accurate responses. Only individuals over 18 residing in Romania were included in the study, which received ethical approval from the University of Medicine and Pharmacy in Craiova.

    The questionnaire’s validation involved a pilot study with 170 participants, overseen by experts in urology, nutrition, and survey design. Adjustments were made for clarity and precision, achieving a Cronbach’s α of 0.86 for consistency.

    The study used Cochran’s formula to determine a sample size of 601, ensuring representative data with a 95% confidence level.

    Following data collection, 1033 valid responses were analyzed. The questionnaire’s reliability was reaffirmed by a Cronbach α coefficient of 0.86. Descriptive statistics provided a baseline overview of the participants, while the chi-square test and correspondence analysis evaluated the impact of various factors on urinary infection frequency.

    Multinomial logistic regression was employed to assess the influence of dietary habits on infection rates. The statistical analysis, ensuring significance at p-values less than 0.05, was conducted using XLSTAT and SPSS software, ensuring a thorough and reliable exploration of the study’s objectives.

    Study results 

    In the study, researchers gathered 1,103 valid responses predominantly from women, who made up 80.1% of the participants.

    Analysis of the anthropometric data revealed that 46.6% of respondents were of normal weight, predominantly women, whereas a significant proportion of male respondents were overweight or obese.

    The study found that urinary infections were more common among women, a fact reflected in the gender distribution of the participants. Most respondents, 76.2%, were under 45 years old, and most hailed from urban areas, likely due to higher online activity in these regions.

    Over 80% of the participants had postsecondary education or higher. In terms of employment, the largest group comprised those who commuted to work or worked in a hybrid mode, while a small fraction worked remotely.

    The study found that individuals aged 26-35 were most prone to urinary infections, while those 18-25 reported the least.

    It revealed a link between infection frequency and factors like sexual contact and showed that healthier diets, especially among women over 45, correlated with lower infection rates.

    Further analysis using multiple linear regression showed that age, education level, weight, and urinary infection frequency significantly influenced dietary choices.

    Younger individuals, rural residents, and those with lower education levels were more likely to adhere to an unhealthy diet. Additionally, underweight individuals and those with frequent urinary infections also tended towards less healthy dietary habits.

    Sex and age were also significant factors in the frequency of UTIs. Women, especially in the 26–35 age group, reported more frequent infections.

    In terms of treatment, many respondents first sought over-the-counter remedies, with some turning to medical consultation only after self-medication failed. Antibiotics and antifungals were common treatments, with antibiograms used frequently by those with recurrent infections.

    The study also noted that common symptoms of urinary infections included frequent urination, burning sensations, and pain. Natural treatments like cranberry-based products and herbal teas were popular among respondents.

    Sedentary lifestyles were linked to more frequent infections, highlighting the role of physical activity in preventing urinary infections.

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  • Study reveals impact of lantibiotic preservatives on gut microbiome

    Study reveals impact of lantibiotic preservatives on gut microbiome

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    Food manufacturers often add preservatives to food products to keep them fresh. A primary purpose of these preservatives is to kill microbes that could break down and otherwise spoil the food. Common additives like sugar, salt, vinegar and alcohol have been used as preservatives for centuries, but modern-day food labels now reveal more unfamiliar ingredients such as sodium benzoate, calcium propionate, and potassium sorbate.

    Bacteria produce chemicals called bacteriocins to kill microbial competitors. These chemicals can serve as natural preservatives by killing potentially dangerous pathogens in food. Lanthipeptides, a class of bacteriocins with especially potent antimicrobial properties, are widely used by the food industry and have become known as “lantibiotics” (a scientific portmanteau of lanthipeptide and antibiotics).

    Despite their widespread use, however, little is known about how these lantibiotics affect the gut microbiomes of people who consume them in food. Microbes in the gut live in a delicate balance, and commensal bacteria provide important benefits to the body by breaking down nutrients, producing metabolites, and-;importantly-;protecting against pathogens. If too many commensals are indiscriminately killed off by antimicrobial food preservatives, opportunistic pathogenic bacteria might take their place and wreak havoc-;a result no better than eating contaminated food in the first place.

    Effects on good and bad bacteria

    A new study published in ACS Chemical Biology by scientists from the University of Chicago found that one of the most common classes of lantibiotics has potent effects both against pathogens and against the commensal gut bacteria that keep us healthy.

    Nisin is a popular lantibiotic used in everything from beer and sausage to cheese and dipping sauces. It is produced by bacteria that live in the mammary glands of cows, but microbes in the human gut produce similar lantibiotics too. Zhenrun “Jerry” Zhang, PhD, a postdoctoral scholar in the lab of Eric Pamer, MD, the Donald F. Steiner Professor of Medicine and Director of the Duchossois Family Institute at UChicago, wanted to study the impact of such naturally-produced lantibiotics on commensal gut bacteria.

    Nisin is, in essence, an antibiotic that has been added to our food for a long time, but how it might impact our gut microbes is not well studied. Even though it might be very effective in preventing food contamination, it might also have a greater impact on our human gut microbes.”


    Zhenrun “Jerry” Zhang, PhD, postdoctoral scholar

    He and his colleagues mined a public database of human gut bacteria genomes and identified genes for producing six different gut-derived lantibiotics that closely resemble nisin, four of which were new. Then, in collaboration with Wilfred A. van der Donk, PhD, the Richard E. Heckert Endowed Chair in Chemistry at the University of Illinois Urbana-Champaign, they produced versions of these lantibiotics to test their effects on both pathogens and commensal gut bacteria. The researchers found that while the different lantibiotics had varying effects, they killed pathogens and commensal bacteria alike.

    “This study is one of the first to show that gut commensals are susceptible to lantibiotics, and are sometimes more sensitive than pathogens,” Zhang said. “With the levels of lantibiotics currently present in food, it’s very probable that they might impact our gut health as well.”

    Harnessing the power of lantibiotics

    Zhang and his team also studied the structure of peptides in the lantibiotics to better understand their activity, in the interest of learning how to use their antimicrobial properties for good. For example, in another study, the Pamer lab showed that a consortium of four microbes, including one that produces lantibiotics, help protect mice against antibiotic-resistant Enterococcus infections. They are also studying the prevalence of lantibiotic-resistant genes across different populations of people to better understand how such bacteria can colonize the gut under different conditions and diets.

    “It seems that lantibiotics and lantibiotic-producing bacteria are not always good for health, so we are looking for ways to counter the potential bad influence while taking advantage of their more beneficial antimicrobial properties,” Zhang said.

    Source:

    Journal reference:

    Zhang, Z. J., et al. (2024). Activity of Gut-Derived Nisin-like Lantibiotics against Human Gut Pathogens and Commensals. ACS Chemical Biology. doi.org/10.1021/acschembio.3c00577.

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  • IU surgeon-scientist investigates the role of sinus microbiome in chronic rhinosinusitis

    IU surgeon-scientist investigates the role of sinus microbiome in chronic rhinosinusitis

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    An Indiana University School of Medicine surgeon-scientist is leading a multi-institutional grant investigating the role of the sinus microbiome in chronic rhinosinusitis, an inflammatory disease that causes the lining of the sinuses to swell. The research team will study biospecimens from human sinus surgery patients in the lab and examine how bacteria in the microbiome shape the disease process and might offer novel therapeutic strategies.

    Vijay Ramakrishnan, MD, professor of otolaryngology-;head and neck surgery and a primary member of Stark Neurosciences Research Institute, has spent over a decade investigating the microbiome. The five-year, $2.9 million grant from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, is a first-of-its-kind grant studying the physiological effect of the sinus microbiome on chronic rhinosinusitis.

    The microbiome is an accumulation of microorganisms-;bacteria, fungi and viruses-;that live within areas of the human body, such as the gut and sinus cavities. These microbes can shape a person’s health, predispose people to disease, act as disease modifiers and influence how people respond to specific treatments. In chronic rhinosinusitis, scientists believe microbes and bacteria play a role in sinus inflammation beyond a person’s traditional sinus infection.

    The upper airway is heavily colonized with bacteria, and the different types of influence immune processes and the general function of the surface lining. If we can steer the microbiome into a favorable healthy state, there are some functions that we can influence to maybe get us better treatment results.”


    Vijay Ramakrishnan, MD, professor of otolaryngology-;head and neck surgery and a primary member of Stark Neurosciences Research Institute

    Ramakrishnan will work with researchers at the University of Colorado School of Medicine, led by Daniel Frank, PhD. Ramakrishnan started his research of the microbiome when he was a faculty member at the University of Colorado; he joined IU School of Medicine in January 2022.

    Chronic rhinosinusitis affects nearly 10% of adults in the United States. Most patients manage the disease medically through sinus rinses, nasal spray medications and allergy treatments. It’s estimated, however, that 15% of chronic rhinosinusitis patients pursue sinus surgery, where most cases result in subpar outcomes, Ramakrishnan said. The volume of chronic rhinosinusitis cases, he added, is expected to rise due to climate change, pollution and western diet.

    Antibiotics have long been prescribed for chronic rhinosinusitis-;it’s one of the top conditions for antibiotic use, according to the Centers for Disease Control and Prevention-;but they haven’t shown to be effective in treating most patients, Ramakrishnan said. The disease is now viewed as inflammatory rather than infectious, creating a need to develop new treatment strategies.

    “This problem is very prevalent in adults. There’s only a handful of therapies, and they work about 75% of the time,” Ramakrishnan said. “Understanding the role of microbiome in this disease and focusing clinical approaches to restrict antibiotic use are our two main health outcomes.”

    Researchers will collect biospecimens of surgical patients to investigate host-microbial processes in airway mucosal immunology. They’ll also use cell cultures to test how various microorganisms impact disease processes and initiate specific immune responses.

    The grant also supports a longitudinal multi-institutional human intervention study of chronic rhinosinusitis surgical patients. The research team will investigate patient outcomes, medication use and how the microbiome of patients changes over time, Ramakrishnan said.

    Ramakrishnan said this study moves beyond prior small observational studies by defining molecular, cellular, and immunological processes using a multi-omics approach, which incorporates data derived from transcriptomics and metabolomics.

    The team will collaborate with Thomas O’Connell, PhD, associate professor of otolaryngology-;head and neck surgery, to conduct tissue metabolomics and with IU network scientists at the Luddy School of Informatics, Computing, and Engineering at IU Bloomington to do a physics-based approach to understand networks of interaction between disease and patient outcomes and tissue-level multi-omics.

    “We’re trying to figure out which chronic rhinosinusitis patients have a microbial component that we can influence, to steer them to better outcomes and allow their own bodies to restore health, thereby limiting antibiotic use and number of interventions,” Ramakrishnan said.

    Source:

    Indiana University School of Medicine

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  • Scientists coax a deadly bacterium to destroy itself from the inside out

    Scientists coax a deadly bacterium to destroy itself from the inside out

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    Northwestern University researchers have successfully coaxed a deadly pathogen to destroy itself from the inside out.

    In the new study, researchers modified DNA from a bacteriophage or “phage,” a type of virus that infects and replicates inside of bacteria. Then, the research team put the DNA inside Pseudomonas aeruginosa (P. aeruginosa), a deadly bacterium that is also highly resistant to antibiotics. Once inside the bacterium, the DNA bypassed the pathogen’s defense mechanisms to assemble into virions, which sliced through the bacterium’s cell to kill it.

    Building on a growing interest in “phage therapies,” the experimental work represents a critical step toward engineering designer viruses as new therapeutics to kill antibiotic-resistant bacteria. It also reveals vital information about the innerworkings of phages, a little-studied area of biology.

    The study will be published on Wednesday (Jan. 24) in the journal Microbiology Spectrum.

    “Antimicrobial resistance is sometimes referred to as the ‘silent pandemic,’” said Northwestern’s Erica Hartmann, who led the work. “The numbers of infections and deaths from infections are increasing worldwide. It’s a massive problem. Phage therapy has emerged as an untapped alternative to our reliance on using antimicrobials. But, in many ways, phages are microbiology’s ‘final frontier.’ We don’t know much about them. The more we can learn about how phage work, the more likely we can engineer more effective therapeutics. Our project is cutting-edge in that we are learning about phage biology in real time as we engineer them.”

    An indoor microbiologist, Hartmann is an associate professor of civil and environmental engineering at Northwestern’s McCormick School of Engineering and a member of the Center for Synthetic Biology.

    Desperate need for antibiotic alternatives

    Associated with an increase in antimicrobial use, the rise of antibacterial resistance is an urgent and growing threat to the global population. According to the Centers for Disease Control and Prevention (CDC), nearly 3 million antimicrobial-resistant infections occur each year in the United States alone, with more than 35,000 people dying as a result.

    The growing crisis has motivated researchers to look for alternatives to antibiotics, which are continually losing effectiveness. In recent years, researchers have started to explore phage therapies. But even though billions of phages exist, scientists know very little about them.

    For every bacterium that exists, there are dozens of phages. So, there is an astronomically large number of phages on Earth, but we only understand a handful of them. We haven’t necessarily had the motivation to really study them. Now, the motivation is there, and we are increasing the number of tools we have to dedicate to their study.”


    Erica Hartmann, Northwestern University

    Treatment without side effects

    To explore potential phage therapies, researchers either pinpoint or modify an existing virus to selectively target a bacterial infection without disrupting the rest of body. Ideally, scientists one day could tailor a phage therapeutic to infect a specific bacterium and design “a la carte” therapeutics with precise traits and characteristics to treat individual infections.

    “What’s powerful about phage is it can be very specific in the way that antibiotics are not,” Hartmann said. “If you take an antibiotic for a sinus infection, for example, it disrupts your entire gastrointestinal tract. A phage therapy can be designed to affect only the infection.”

    While other researchers have investigated phages therapies, almost all of those studied have focused on using phages to infect Escherichia coli. Hartmann, however, decided to focus on P. aeruginosa, one of the five most deadly human pathogens. Particularly dangerous for people with compromised immune systems, P. aeruginosa is a leading cause of hospital infections, often infecting patients with burn or surgery wounds as well as lungs in people with cystic fibrosis.

    “It is one of the highest priority, multi-drug resistant pathogens that many people are really concerned about,” Hartmann said. “It is extremely drug resistant, so there is an urgent need to develop alternative therapeutics for it.”

    Mimicking infection, bypassing defenses

    In the study, Hartmann and her team started with P. aeruginosa bacteria and purified DNA from several phages. Then, they used electroporation -; a technique that delivers short, high-voltage pulses of electricity -; to poke temporary holes in the bacteria’s outer cell. Through these holes, phage DNA entered the bacteria to mimic the process of infection.

    In some cases, the bacteria recognized the DNA as a foreign object and shredded the DNA to protect itself. But after using synthetic biology to optimize the process, Hartmann’s team was able to knock out the bacteria’s antiviral self-defense mechanisms. In these cases, the DNA successfully carried information into the cell, resulting in virions that killed the bacteria.

    “Where we were successful, you can see dark spots on the bacteria,” Hartmann said. “This is where the viruses burst out of the cells and killed all the bacteria.”

    After this success, Hartmann’s team introduced DNA from two more phages that are naturally unable to infect their strain of P. aeruginosa. Yet again, the process worked.

    Phage manufacturing in a cell

    Not only did the phage kill the bacteria, the bacteria also ejected billions more phages. These phages can then be used to kill other bacteria, like those causing an infection.

    Next, Hartmann plans to continue modifying phage DNA to optimize potential therapies. For now, her team is studying the phages expelled from the P. aeruginosa.

    “This is an important piece in making phage therapies,” she said. “We can study our phage in order to decide which ones to develop and eventually mass produce them as a therapeutic.”

    The study, “A synthetic biology approach to assemble and reboot clinically relevant Pseudomonas aeruginosa tailed phages,” was supported by the Walder Foundation, the National Science Foundation and the National Institutes of Health.

    Source:

    Journal reference:

    Ipoutcha, T., et al. (2024) A synthetic biology approach to assemble and reboot clinically relevant Pseudomonas aeruginosa tailed phages. Microbiology Spectrum. doi.org/10.1128/spectrum.02897-23.

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  • High diet quality in early life associated with reduced risk of IBD

    High diet quality in early life associated with reduced risk of IBD

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    A high quality diet at the age of 1 may curb the subsequent risk of inflammatory bowel disease, suggests a large long term study, published online in the journal Gut.

    Plenty of fish and vegetables and minimal consumption of sugar-sweetened drinks at this age may be key to protection, the findings indicate.

    A linked editorial suggests that it may now be time for doctors to recommend a ‘preventive’ diet for infants, given the mounting evidence indicative of biological plausibility.

    Cases of inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, are increasing globally. Although there is no obvious explanation for this trend, changes in dietary patterns are thought to have a contributory role, because of their impact on the gut microbiome.

    While various studies have looked at the influence of diet on IBD risk in adults, there is little in the way of research on the potential influence of early childhood diet on risk.

    In a bid to plug this knowledge gap, the researchers drew on survey data from the All Babies in Southeast Sweden study (ABIS) and The Norwegian Mother, Father and Child Cohort Study (MoBa).

    ABIS includes 21,700 children born between October 1997 and October 1999; MoBa includes 114, 500 children, 95,200 mothers, and 75,200 fathers recruited from across Norway between 1999 and 2008.

    Parents were asked specific questions about their children’s diet when they were aged 12-18 months and 30-36 months. The final analysis included dietary information for 81,280 1 year olds: 11,013 (48% girls) from ABIS and 70, 267 (49% girls) from MoBa.

    Diet quality, gleaned from measuring intake of meat, fish, fruit, vegetables, dairy, sweets, snacks, and drinks, was assessed using a modified version of the Healthy Eating Index (HEI) scoring system, adapted for children. The weekly frequency of specific food groups was also assessed.

    Higher diet quality-;a higher intake of vegetables, fruit, and fish, and a lower intake of meat, sweets, snacks, and drinks-;was reflected in a higher HEI score.The total score was divided into thirds to indicate a low, medium, or high quality diet. 

    Data on age at weaning, antibiotic use, and formula feed intake were also reported at age 12 (ABIS) and 18 months (MoBa).

    The children’s health was monitored for an average of 21 (ABIS) and 15 (MoBa) years from the age of 1 until 31 December 2020-21. 

    During this period, 307 children were diagnosed with IBD (131 with Crohn’s disease; 97 with ulcerative colitis; and 79 with unclassified IBD). The average age at diagnosis was 17 (ABIS) and 12 (MoB).

    Medium and high quality diets at the age of 1 were associated with an overall 25% lower risk of IBD compared with a low quality diet at this age, after adjusting for potentially influential factors, such as parental history of IBD, the child’s sex, ethnic origin, and education and co-existing conditions in the mother.

    Specifically, high fish intake at the age of 1 was associated with a lower overall risk compared with its opposite, and a 54% lower risk of ulcerative colitis in particular. 

    Higher vegetable intake at 1 year of age was also associated with a reduced risk of IBD. On the other hand, consumption of sugar-sweetened drinks was associated with a 42% heightened risk. 

    There were no obvious associations between any of the other food groups, including meat, dairy, fruit, grains, potatoes and foods high in sugar and/or fat, and overall IBD or Crohn’s disease or ulcerative colitis risks.

    By the age of 3, only high fish intake was associated with reduced IBD risk, and ulcerative colitis in particular.

    The findings remained unchanged after accounting for household income and the child’s formula intake and antibiotic use by the age of 1.

    This is an observational study, and as such, can’t establish cause. And the researchers acknowledge that while the ABIS participation rate was high (79%), it was only 41% for MoBa. And because Sweden and Norway are two high-income countries, findings may not be generalisable to low- or middle-income countries with other dietary habits, they add.

    “While non-causal explanations for our results cannot be ruled out, these novel findings are consistent with the hypothesis that early-life diet, possibly mediated through changes in the gut microbiome, may affect the risk of developing IBD,” they conclude.

    In a linked editorial, gastroenterologist Dr Ashwin Ananthakrishnan of Massachusetts General Hospital, Boston, USA, cautions that the questionnaires didn’t capture elements, such as additives and emulsifiers which are common in baby food, and which may contribute to the development of IBD. 

    Accurate measures of food intake in infants and young children are inherently fraught with difficulty, he adds.

    But he goes on to say that it may nevertheless be time to recommend a ‘preventive’ diet, particularly as this is likely to have other health benefits.

    “Despite the absence of gold standard interventional data demonstrating a benefit of dietary interventions in preventing disease, in my opinion, it may still be reasonable to suggest such interventions to motivated individuals that incorporate several of the dietary patterns associated with lower risk of IBD from this and other studies.

    “This includes ensuring adequate dietary fiber, particularly from fruit and vegetables, intake of fish, minimizing sugar-sweetened beverages and preferring fresh over processed and ultra-processed foods and snacks.”

    Source:

    Journal reference:

    Guo, A., et al. (2024). Early-life diet and risk of inflammatory bowel disease: a pooled study in two Scandinavian birth cohorts. Gut. doi.org/10.1136/gutjnl-2023-330971.

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