Tag Archives: Antiviral Drug

Microbiology

Resistant bacteria are a global problem. Now researchers may have found the solution

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Staphylococcus aureus. You may have had it in connection with a wound infection. In most cases, it will pass without treatment, while severe cases may require antibiotics, which kills the bacteria. This is the case for the majority of the population. In fact, many of us — though we feel perfectly fine — carry staphylococci in the nose, a good, moist environment in which the bacteria thrive.

However, more and more staphylococci are becoming resistant to antibiotics (also known as multi resistant staphylococcus aureus or MRSA), and these infections can be difficult to treat.

“Antibiotics resistance is an increasing problem, especially on a global scale. And when you have this relatively simple infection which suddenly cannot be treated with antibiotics, the situation can turn serious, sometimes life-threatening,” says Professor Niels Ødum from the LEO Foundation Skin Immunology Research Center at the University of Copenhagen.

Therefore, all over the world, a lot of resources are being invested in fighting antibiotics resistance in staphylococcus aureus infections, and a new study among skin lymphoma patients has produced positive results. A new substance called endolysins has proven capable of killing both resistant and non-resistant staphylococcus aureus — without the need for antibiotics. But we will get back to that.

The discovery is good news to patients with a weak immune system to whom a staphylococcus aureus infection can be serious and, at worst, fatal. But it also adds to the knowledge we have of other forms of treatment.

“To people who are severely ill with e.g. skin lymphoma, staphylococci can be a huge, sometimes insoluble problem, as many are infected with a type of staphylococcus aureus that is resistant to antibiotics,” says Niels Ødum and adds:

“That is why we are careful not to give antibiotics to everyone, because we do not want to have to deal with more resistant bacteria. Therefore, it is important that we find new ways of treating — and not the least to prevent — these infections.”

New substance may be the answer

In some patients, a staphylococcus aureus will cause the cancer to worsen. And even though antibiotics appear to work in some cases, it is not without its problems.

“We can tell that giving high doses of antibiotics to patients with serious infections causes their health, skin and cancer symptoms to improve. But once we stop giving them antibiotics, the symptoms and staphylococci quickly return. Patients experience many adverse effects, and some risk getting resistant bacteria,” says Niels Ødum.

Therefore, treating staphylococcus aureus can be tricky. At worst, cancer patients may die of an infection which doctors are unable to treat.

And this is where endolysins enter the scene, as this new substance may be part of the solution to antibiotics resistance like MRSA.

“This particular endolysin is a brand new, artificially produced enzyme that has been improved several times and designed as a new drug,” explains Postdoc Emil Pallesen, who is first author of the study. He adds:

“The great thing about this enzyme is that it has been designed to penetrate the wall of staphylococcus aureus. This enables it to target and kill the harmful staphylococcus and leave harmless skin bacteria unharmed.”

And that is what made the researchers decide to test the new substance; they expected it to be able to kill both resistant and non-resistant staphylococcus bacteria.

“We have been testing the substance on skin samples from patients, and it does appear to kill staphylococcus aureus from patients. Endolysins do not care whether the bacterium is resistant to antibiotics or not, because it does not work in the same way as antibiotics,” says Niels Ødum and adds:

“The really good news is that our lab tests have showed that endolysins do not just eradicate staphylococcus aureus; they also inhibit their ability to promote cancer growth.”

  • Emil M.H. Pallesen, Maria Gluud, Chella K. Vadivel, Terkild B. Buus, Bob de Rooij, Ziao Zeng, Sana Ahmad, Andreas Willerslev-Olsen, Christian Röhrig, Maria R. Kamstrup, Lene Bay, Lise Lindahl, Thorbjørn Krejsgaard, Carsten Geisler, Charlotte M. Bonefeld, Lars Iversen, Anders Woetmann, Sergei B. Koralov, Thomas Bjarnsholt, Johan Frieling, Mathias Schmelcher, Niels Ødum. Endolysin inhibits skin colonization by patient-derived Staphylococcus aureus and malignant T cell activation in cutaneous T cell lymphoma. Journal of Investigative Dermatology, 2023; DOI: 10.1016/j.jid.2023.01.039

    • University of Copenhagen – The Faculty of Health and Medical Sciences
    Microbiology

    A quick new way to screen virus proteins for antibiotic properties

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    As conventional antibiotics continue to lose effectiveness against evolving pathogens, scientists are keen to employ the bacteria-killing techniques perfected by bacteriophages, the viruses that infect bacteria.

    One major challenge standing in their way is the difficulty of studying individual bacteriophage (phage) proteins and determining precisely how the virus wields these tools to kill their host bacteria. New research from Lawrence Berkeley National Laboratory (Berkeley Lab) could help speed things along.

    “We developed a high-throughput genetic screening approach that can identify the part of the bacterial cell targeted by a potent type of phage weapon called ‘single-gene lysis proteins,'” said Vivek Mutalik, a staff scientist in Berkeley Lab’s Biosciences Area and co-author on a new study describing the work in Nature Chemical Biology. “With rising antibiotic resistance, we urgently need antibiotic alternatives. Some of the smallest phages that we know of code for single-gene lysis proteins (Sgls), also known as ‘protein antibiotics,’ to inhibit key components of bacterial cell wall production that, when disrupted, consistently kill the cell.”

    There appears to be at least one type of phage for every known strain of bacteria, and they are thought to be the most abundant biological entities on Earth. In fact, there are an estimated 1031 phage particles on the planet right now, or the equivalent of one trillion phages for every grain of sand. Each of these phages evolve alongside their chosen host strain, allowing them to counter bacterial resistance traits, as they arise, with improved biological weaponry.

    This massive abundance, specificity, and efficacy means that there are plenty around to study, and that we should theoretically be able to use phages to control any harmful microbe. Phages are also harmless to non-bacterial cells, another reason they are so appealing as medicines and biocontrol tools.

    The problem arises when trying to isolate a single phage from the environment and determine which microbe it targets and how. Scientists are often unable to assess phage-bacteria battles based on genomic sequence alone or study them in action because many bacteria can’t be cultured in a lab — and even if they could, there’s an inherent catch-22 of needing to know ahead of time which bacteria to culture in order to study the phages that infect and kill them.

    To sidestep these obstacles and identify the cellular targets of Sgls, Mutalik and his colleagues used a technology the team previously invented called Dual-Barcoded Shotgun Expression Library Sequencing (Dub-seq). Dub-seq allows scientists to employ a coded library of DNA fragments to investigate how unknown genes function, and can be applied to complicated environmental samples that contain the DNA of many organisms — no culturing needed. In this study, the authors used six Sgls from six phages that infect different bacteria and identified the part of the bacterial cell wall or supporting molecules that each Sgl attacks. In collaboration with scientists from Texas A&M University, they conducted a detailed characterization of the function of one Sgl.

    This work showed that the Sgl proteins target pathways for cell wall building that arose very early in the evolutionary history of bacteria and are still used by nearly all bacteria (including pathogenic bacteria). Since the Sgl proteins attack such fundamental and ubiquitous targets, they can kill bacteria other than the phage’s target strain — confirming they have great potential as antibiotics.

    “Phages are extraordinary innovators when it comes to destroying bacteria. We’re really excited to uncover novel bacterial pathogen-targeting mechanisms that could be leveraged into therapies,” said first author Benjamin Adler, a postdoctoral fellow in Jennifer Doudna’s lab at UC Berkeley.

    Now that the team has evaluated the Dub-seq approach for tackling this question, they can apply it to the thousands of single-gene lysis producing phages awaiting characterization in environmental samples that the team has collected from the ocean, soils, and even the human gut. The inspiration for the next breakthrough medicine could be in there, waiting.

  • Benjamin A. Adler, Karthik Chamakura, Heloise Carion, Jonathan Krog, Adam M. Deutschbauer, Ry Young, Vivek K. Mutalik, Adam P. Arkin. Multicopy suppressor screens reveal convergent evolution of single-gene lysis proteins. Nature Chemical Biology, 2023; DOI: 10.1038/s41589-023-01269-7

    • DOE/Lawrence Berkeley National Laboratory
    Microbiology

    How to edit the genes of nature’s master manipulators

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    CRISPR, the Nobel Prize-winning gene editing technology, is poised to have a profound impact on the fields of microbiology and medicine yet again.

    A team led by CRISPR pioneer Jennifer Doudna and her longtime collaborator Jill Banfield has developed a clever tool to edit the genomes of bacteria-infecting viruses called bacteriophages using a rare form of CRISPR. The ability to easily engineer custom-designed phages — which has long eluded the research community — could help researchers control microbiomes without antibiotics or harsh chemicals, and treat dangerous drug-resistant infections. A paper describing the work was recently published in Nature Microbiology.

    “Bacteriophages are some of the most abundant and diverse biological entities on Earth. Unlike prior approaches, this editing strategy works against the tremendous genetic diversity of bacteriophages,” said first author Benjamin Adler, a postdoctoral fellow in Doudna’s lab. “There are so many exciting directions here — discovery is literally at our fingertips!”

    Bacteriophages, also simply called phages, insert their genetic material into bacterial cells using a syringe-like apparatus, then hijack the protein-building machinery of their hosts in order to reproduce themselves — usually killing the bacteria in the process. (They’re harmless to other organisms, including us humans, even though electron microscopy images have revealed that they look like sinister alien spaceships.)

    CRISPR-Cas is a type of immune defense mechanism that many bacteria and archaea use against phages. A CRISPR-Cas system consists of short snippets of RNA that are complementary to sequences in phage genes, allowing the microbe to recognize when invasive genetic material has been inserted, and scissor-like enzymes that neutralize the phage genes by cutting them into harmless pieces, after being guided into place by the RNA.

    Over millennia, the perpetual evolutionary battle between phage offense and bacterial defense forced phages to specialize. There are a lot of microbes, so there are also a lot of phages, each with unique adaptations. This astounding diversity has made phage editing difficult, including making them resistant to many forms of CRISPR, which is why the most commonly used system — CRISPR-Cas9 — doesn’t work for this application.

    “Phages have many ways to evade defenses, ranging from anti-CRISPRs to just being good at repairing their own DNA,” said Adler. “So, in a sense, the adaptations encoded in phage genomes that make them so good at manipulating microbes are the exact same reason why it has been so difficult to develop a general-purpose tool for editing their genomes.”

    Project leaders Doudna and Banfield have developed numerous CRISPR-based tools together since they first collaborated on an early investigation of CRISPR in 2008. That work — performed at Lawrence Berkeley National Laboratory (Berkeley Lab) — was cited by the Nobel Prize committee when Doudna and her other collaborator, Emmanuelle Charpentier, received the prize in 2020. Doudna and Banfield’s team of Berkeley Lab and UC Berkeley researchers were studying the properties of a rare form of CRISPR called CRISPR-Cas13 (derived from a bacterium commonly found in the human mouth) when they discovered that this version of the defense system works against a huge range of phages.

    The phage-fighting potency of CRISPR-Cas13 was unexpected given how few microbes use it, explained Adler. The scientists were doubly surprised because the phages it defeated in testing all infect using double-stranded DNA, but the CRISPR-Cas13 system only targets and chops single-stranded viral RNA. Like other types of viruses, some phages have DNA-based genomes and some have RNA-based genomes. However, all known viruses use RNA to express their genes. The CRISPR-Cas13 system effectively neutralized nine different DNA phages that all infect strains of E. coli, yet have almost no similarity across their genomes.

    According to co-author and phage expert Vivek Mutalik, a staff scientist in Berkeley Lab’s Biosciences Area, these findings indicate that the CRISPR system can defend against diverse DNA-based phages by targeting their RNA after it has been converted from DNA by the bacteria’s own enzymes prior to protein translation.

    Next, the team demonstrated that the system can be used to edit phage genomes rather than just chop them up defensively.

    First, they made segments of DNA composed of the phage sequence they wanted to create flanked by native phage sequences, and put them into the phage’s target bacteria. When the phages infected the DNA-laden microbes, a small percentage of the phages reproducing inside the microbes took up the altered DNA and incorporated it into their genomes in place of the original sequence. This step is a longstanding DNA editing technique called homologous recombination. The decades-old problem in phage research is that although this step, the actual phage genome editing, works just fine, isolating and replicating the phages with the edited sequence from the larger pool of normal phages is very tricky.

    This is where the CRISPR-Cas13 comes in. In step two, the scientists engineered another strain of host microbe to contain a CRISPR-Cas13 system that senses and defends against the normal phage genome sequence. When the phages made in step one were exposed to the second-round hosts, the phages with the original sequence were defeated by the CRISPR defense system, but the small number of edited phages were able to evade it. They survived and replicated themselves.

    Experiments with three unrelated E. coli phages showed a staggering success rate: more than 99% of the phages produced in the two-step processes contained the edits, which ranged from enormous multi-gene deletions all the way down to precise replacements of a single amino acid.

    “In my opinion, this work on phage engineering is one of the top milestones in phage biology,” said Mutalik. “As phages impact microbial ecology, evolution, population dynamics, and virulence, seamless engineering of bacteria and their phages has profound implications for foundational science, but also has the potential to make a real difference in all aspects of the bioeconomy. In addition to human health, this phage engineering capability will impact everything from biomanufacturing and agriculture to food production.”

    Buoyed by their initial results, the scientists are currently working to expand the CRISPR system to use it on more types of phages, starting with ones that impact microbial soil communities. They are also using it as a tool to explore the genetic mysteries within phage genomes. Who knows what other amazing tools and technologies can be inspired by the spoils of microscopic war between bacteria and virus?

    This research was funded by the Department of Energy Microbial Community Analysis & Functional Evaluation in Soils (m-CAFES) Scientific Focus Area. Jill Banfield is a professor of Earth and Planetary Science and Environmental Science, Policy, & Management at UC Berkeley as well as a faculty scientist in Berkeley Lab’s Biosciences Area and an affiliate in the Earth and Environmental Sciences Area. Jennifer Doudna is a professor in the Molecular and Cell Biology and Chemistry departments at UC Berkeley and a faculty scientist in Berkeley Lab’s Biosciences Area.

    Story Source:

    Materials provided by DOE/Lawrence Berkeley National Laboratory. Original written by Aliyah Kovner. Note: Content may be edited for style and length.

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    Journal Reference:

  • Benjamin A. Adler, Tomas Hessler, Brady F. Cress, Arushi Lahiri, Vivek K. Mutalik, Rodolphe Barrangou, Jillian Banfield, Jennifer A. Doudna. Broad-spectrum CRISPR-Cas13a enables efficient phage genome editing. Nature Microbiology, 2022; 7 (12): 1967 DOI: 10.1038/s41564-022-01258-x

    • DOE/Lawrence Berkeley National Laboratory
    Microbiology

    Miracles Start in the Lab: the quest to find a vaccine to cure AIDS

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    Danielle Ellis, B.Sc.Interview conducted by Danielle Ellis, B.Sc.Nov 30 2022
    Thought LeadersDr. Larry CoreyProfessor and President and Director EmeritusFred Hutch Cancer Center

    To commemorate World AIDS Day, News Medical spoke to Dr. Larry Corey, an internationally renowned expert in virology, immunology, and vaccine development, and the former president and director of Fred Hutch, about his work within the field of HIV/AIDS research and vaccine development. 

    Please can you introduce yourself and tell us about your background in virology, immunology, and vaccine development?  

    I’m Dr. Larry Corey. I am a Professor at the University of Washington and Fred Hutchinson Cancer Center. I am a virologist by training. I have worked in the field of HIV since the inception of the recognition of the virus. Initially, I was the leader of the US government’s AIDS Clinical Trials Group, which was devoted to antiviral chemotherapy. I was lucky early in my career to be involved in developing the first effective antiviral drug called Acyclovir, which was for herpes virus infections, especially genital herpes.

    I switched my interests in the late 1990s from therapy to try and develop an HIV vaccine and founded the HIV Vaccine Trials Network with my friend and colleague Tony Fauci. We’ve worked together to develop an HIV vaccine and set up a network within the US of investigators to tackle the immunology of HIV, which has been very formidable. The network has been where probably 80 or 90% of the HIV vaccine clinical trials have been conducted worldwide over the last 20 years.

    How have you seen the field of HIV/AIDS research change in this time? How have patient outcomes changed?

    HIV is still a pandemic illness. We still have 1.4 million new infections each year. We have a growing number of people living with AIDS, and it is still a perfect storm. You acquire it subclinically, transmit it subclinically, and get it from people you don’t suspect have it. We still need better prevention methods.

    Antiretrovirals have saved more lives than any other medical procedure or medical group of therapies in the last 50 or 60 years. We went from a disease that killed everybody to now a disease that, if you take the pills, you can live a normal lifespan essentially. That’s an amazing feat that occurred in the decade from the virus’s isolation.

    Image Credit: PENpics Studio/Shutterstock.com

    Image Credit: PENpics Studio/Shutterstock.com

    HIV research has markedly changed and become markedly more sophisticated. We’re cloning B-cells in the germ lines. We’re doing things you couldn’t conceive 40 years ago. Certainly, a vaccine will be needed to end AIDS and have my granddaughters grow up like I grew up, not worrying about AIDS.

    Patient outcomes for treatment have markedly changed. You can live normal lives. But we haven’t made as many inroads in prevention. The reason is that we don’t have a vaccine. When you look at how to prevent disease acquisition on a population basis, it’s only been with a vaccine. So, as hard as it is, the vaccine effort must continue.

    In your lab, you study genetically modified T cells to treat HIV-1. How have recent advancements in cancer treatment influenced the treating HIV/AIDS? How can immunological approaches treat chronic viral infections?

    In oncology, using the cell as an anti-tumor drug in CAR T-cell therapy is the biggest advance. The lab is trying to take those approaches used in cancer and employ them against HIV through these adopted transfer experiments. We think we’ve had some successes, so that’s our area of interest at the moment.

    You are also the principal investigator of the Fred Hutch-based operations center of the COVID-19 Prevention Network. How has the COVID-19 pandemic impacted HIV/AIDS research?

    People working in HIV and the infrastructure from HIV helped the effort against COVID-19. RNA, used in the COVID-19 mRNA vaccines, can allow experiments to be conducted more quickly because it’s synthetic, and you can make a vaccine and get it into humans by doing an early clinical trial. From the idea to putting a jab in your arm, that’s still not happening as quickly with HIV as it did for COVID-19. Still, it is quicker, and we’re optimistic that this RNA technology will help us develop an HIV vaccine quicker.

    The HVTN’s goal is to develop a safe, effective vaccine to prevent HIV globally. How close are we to actualizing this goal? From a global perspective, what would it mean to have an effective vaccine?

    We make these vaccines that elicit broadly neutralizing antibodies. If we do, we’ll get there because we’ve already proven that broadly neutralizing antibodies can prevent HIV acquisition. Now the issue is how do we get to that target now that we know what the target is? You need to be optimistic. Miracles start in the lab.

    The theme of this year’s World AIDS Day is “Equalize.” What does this theme mean to you personally? What needs to be done to address inequalities and help end AIDS?

    Everybody wants to be healthy. I think equalize is a great word for World AIDS Day. I think HIV has always been a disease of the underdog.

    Image Credit: fizkes/Shutterstock.com

    Image Credit: fizkes/Shutterstock.com

    But words have meaning and should be actionable. I think the word equalize is just another call to how we actualize the tools and maximize the use of the tools we have. COVID-19 has taught us that even if research invents a remarkably good vaccine, the process of implementing this on a population basis is complicated and needs to be equalized between the haves and the have-nots. The sociology and economics of health need to be equalized globally.

    What is next for yourself and your research?

    I’ve got my hands full trying to make an HIV vaccine.

    Where can readers find more information?

    About Dr. Larry Corey

    Dr. Larry Corey is an internationally renowned expert in virology, immunology and vaccine development, and the former president and director of the Fred Hutchinson Cancer Research Center. His research focuses on herpes viruses, HIV, the novel coronavirus and other viral infections, including those associated with cancer. He is principal investigator of the HIV Vaccine Trials Network (HVTN), which conducts studies of HIV vaccines at over 80 clinical trials sites in 16 countries on five continents. Under his leadership, the HVTN has become the model for global, collaborative research. Dr. Corey is also the principal investigator of the Fred Hutch-based operations center of the COVID-19 Prevention Network (CoVPN) and co-leads the Network’s COVID-19 vaccine testing pipeline. The CoVPN is carrying out the large Operation Warp Speed portfolio of COVID-19 vaccines and monoclonal antibodies intended to protect people from COVID-19. 

    Dr. Corey is a member of the US National Academy of Medicine and the American Academy of Arts and Sciences, and was the recipient of the Parran Award for his work in HSV-2, the American Society of Microbiology Cubist Award for his work on antivirals, and the University of Michigan Medical School Distinguished Alumnus Award. He is one of the most highly cited biomedical researchers in the last 20 years and is the author, coauthor or editor of over 1000 scientific publications. 

    Microbiology

    Scientists reveal first close-up look at bats’ immune response to live infection

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    Scientists at Duke-NUS Medical School and colleagues in Singapore have sequenced the response to viral infection in colony-bred cave nectar bats (Eonycteris spelaea) at single-cell resolution. Published in the journal Immunity, the findings contribute to insights into bat immunity that could be harnessed to protect human health.

    Bats harbour many types of viruses. Even when they are infected with viruses deadly to humans, they show no notable signs or symptoms of disease.

    “It is our hope that by understanding how bats’ immune responses protect them from infections, we may find clues that will help humans to better combat viral infections,” explained Dr Akshamal Gamage, Research Fellow with Duke-NUS’ Emerging Infectious Diseases (EID) Programme and a co-first author of the study.

    “And knowing how to better fight viral infections can aid in the development of treatments that will help us to be more bat-like — by falling sick less and ageing better,” added Mr Wharton Chan, an MD-PhD candidate at Duke-NUS who is also a co-first author of the study.

    In this study, the scientists investigated bat immune responses to Malacca virus, a double-stranded RNA virus that uses bats as its natural reservoir. This virus also causes mild respiratory disease in humans.

    The team used single-cell transcriptome sequencing to study lung immune responses to infections at the cellular level, identifying the different types of immune cells in bats — some of which are different from those in other mammals, including humans — and uncovering what they do in response to such viral infections.

    They found that a type of white blood cell, called neutrophils, showed a very high expression of a gene called IDO1, which is known to play a role in mediating immune suppression in humans. The scientists believe that IDO1 expression in cave nectar bats could play an important role in limiting inflammation following infection.

    Dr Feng Zhu, Research Fellow with the EID Programme and a co-first author of the study, said, “We also found marked anti-viral gene signatures in white blood cells known as monocytes and alveolar macrophages, which — in a sense — consume viral particles and then teach T cells how to recognise the virus. This observation is interesting as it shows that bats clearly activate an immune response following infection despite showing few outward symptoms or pathology.”

    The team also identified an unusual diversity and abundance of T cells and natural killer cells — named for their ability to kill tumour cells and cells infected with a virus — in the cave nectar bat, which are broadly activated to respond to the infection.

    “This is the first study that details the bat immune response to in vivo infection at the single-cell transcriptome level,” said Professor Linfa Wang, senior author of the study from the EID Programme. “We believe that our work serves as a key guide to inform further investigations into uncovering the remarkable biology of bats. Moving forward, besides studies into viral disease tolerance, we also hope to uncover clues to longevity from bats as long-lived mammals and also learn how these nectarivorous bats can live on the high sugar diet in nectar without getting diabetes.”

    Story Source:

    Materials provided by Duke-NUS Medical School. Note: Content may be edited for style and length.

    Journal Reference:

  • Akshamal M. Gamage, Wharton O.Y. Chan, Feng Zhu, Yan Ting Lim, Sandy Long, Matae Ahn, Chee Wah Tan, Randy Jee Hiang Foo, Wan Rong Sia, Xiao Fang Lim, Haopeng He, Weiwei Zhai, Danielle E. Anderson, Radoslaw Mikolaj Sobota, Charles-Antoine Dutertre, Lin-Fa Wang. Single-cell transcriptome analysis of the in vivo response to viral infection in the cave nectar bat Eonycteris spelaea. Immunity, 2022; 55 (11): 2187 DOI: 10.1016/j.immuni.2022.10.008

    • Duke-NUS Medical School
    Microbiology

    NIAID awards more than $12 million for the development of antiviral therapies

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    Reviewed by Emily Henderson, B.Sc.Nov 21 2022

    The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, recently awarded more than $12 million to three institutions for the development of antiviral therapies to treat diseases caused by viruses with pandemic potential. NIAID may award approximately $61.5 million total over five years if all contract options are exercised. The new product development contracts are part of the Antiviral Program for Pandemics (APP), which aims to accelerate the discovery, development and manufacturing of antiviral medicines.

    Antivirals are treatments that fight viral infections by acting directly against the virus. Other types of therapies, not the focus of this program, harness the body’s immune system to fight infection. The new contracts will support the development of promising antiviral candidates from late-stage preclinical studies through investigational new drug application-enabling activities and clinical testing.

    Alongside the new product development contracts, NIAID already supports nine Antiviral Drug Discovery (AViDD) Centers for Pathogens of Pandemic Concern. The AViDD Centers conduct research on the early-stage identification and validation of novel viral targets and identification and early-stage characterization of antiviral drug candidates.

    The new product development contracts include:

    Optimization of Broad-Spectrum Filovirus Inhibitors that Target Viral Glycoprotein
    Principal investigator: Terry Bowlin, Ph.D.
    Institute: Microbiotix, Inc., Worcester, Massachusetts
    Base funding amount: $2,069,416
    NIAID contract: 75N93023C00001

    Development of a Novel 2-Pyrimidone (SRI-42718) as a Potent Inhibitor of Chikungunya Virus Infection and Disease
    Principal investigator: Daniel Streblow, Ph.D.
    Institute: Oregon Health and Science University, Portland
    Base funding amount: $4,696,452
    NIAID contract: 75N93023C00002

    Development of an Orally Available Antiviral Drug for Yellow Fever
    Principal investigator: Jinhong Chang, M.D., Ph.D.
    Institute: Baruch S. Blumberg Institute, Doylestown, Pennsylvania
    Base funding amount: $5,493,876
    NIAID contract: 75N93023C00003

    For more information about the APP, please visit: https://www.niaid.nih.gov/research/antivirals.

    Source:

    National Institutes of Health

    Microbiology

    Take probiotics alongside your prescribed antibiotics to reduce damage to your gut microbiome, says the first review of the data

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    Millions of antibiotics are prescribed every year. Although they can be incredibly effective at treating infections, antibiotics usually do not solely target the bacteria that is causing infection. They also kill the harmless bacteria that live in our gut and help us stay healthy. There is evidence that this disruption to the gut microbiome composition can last for up to 2 years after antibiotic treatment. Gastrointestinal symptoms such as diarrhea and bloating are also common side effects of antibiotic use.

    Dr Elisa Marroquin, Assistant Professor at Texas Christian University, USA, and co-author of the paper, explained:

    “Like in a human community, we need people that have different professions because we don’t all know how to do every single job. And so the same happens with bacteria. We need lots of different gut bacteria that know how to do different things.

    “Even though we haven’t come up with a single definition of what is a healthy gut microbiome, one of the constant things we observe in healthy people is that they have a higher level of diversity and more variety of bacteria in the gut.”

    Previous studies demonstrated that taking probiotics can reduce gastrointestinal side effects from antibiotics, but there has been debate over whether taking probiotics alongside antibiotics can also preserve the diversity and composition of microbes in the gut. Some healthcare professionals are reluctant to recommend probiotics alongside antibiotics for fear of further altering the delicate balance of microbes in the patient’s gut.

    A new paper published in the Journal of Medical Microbiology reveals the first systematic review to assess the effect of taking probiotics alongside antibiotics on the diversity and composition of the human gut microbiome. Authored by researchers from the School of Medical and Health Sciences at Tecnológico de Monterrey, University of Texas and Texas Christian University, the review evaluates trends across 29 studies published over the past seven years.

    The authors found that taking probiotics alongside antibiotics can prevent or lessen some antibiotic-induced changes to gut microbiome composition. Probiotics can also help protect species diversity and even restore the populations of some friendly bacteria such as Faecalibacterium prausnitzii, which reduces inflammation and promotes a healthy intestinal barrier.

    Dr Elisa Marroquin said: “When participants take antibiotics, we see several consistent changes in some bacterial species. But when treatment was combined with probiotics, the majority of those changes were less pronounced and some changes were completely prevented.

    “Considering the human data available up to this point, there does not seem to be a reason to withhold a prescription of probiotics when antibiotics are prescribed.”

    Story Source:

    Materials provided by Microbiology Society. Note: Content may be edited for style and length.

    Journal Reference:

  • Melissa Fernández-Alonso, Andrea Aguirre Camorlinga, Sarah E. Messiah, Elisa Marroquin. Effect of adding probiotics to an antibiotic intervention on the human gut microbial diversity and composition: a systematic review. Journal of Medical Microbiology, 2022; 71 (11) DOI: 10.1099/jmm.0.001625

    • Microbiology Society
    Microbiology

    Controlling gut flora can reduce mortality rate in critically ill patients on life support

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    Preventing severe lung infections in mechanically ventilated intensive care patients by applying topical antibiotics to the upper digestive tract results in a clinically meaningful improvement in survival, new research shows.

    The results are being presented during the ‘Hot Topics’ session of the European Society of Intensive Care Medicine annual congress in Paris and simultaneously published in the Journal of the American Medical Association (JAMA).

    Professor John Myburgh AO, lead author and Director of the Critical Care Division at The George Institute for Global Health, said that ventilator-associated pneumonia is a major cause of death and disability in critically ill patients being mechanically ventilated in intensive care units.

    “While the concept of ‘selective decontamination’ of the digestive tract, or ‘SDD’, has been around for decades, this is the first large-scale randomised clinical trial that used a high-quality commercially prepared product specifically designed to prevent ventilator-associated pneumonia in these patients,” he said.

    “In nearly 3,000 patients treated with SDD, we saw a reduction in death of around two percent, equivalent to one death prevented for every 50 patients treated.”

    SDD is an infection-control measure where non-absorbed antibiotics and antifungal agents are applied to the mouth and stomach, combined with a short course of intravenous antibiotics.

    This inhibits the development of ventilator-associated pneumonia caused by harmful bacteria and overgrowth of fungi that normally live in the upper part of the gut but enter and infect the lungs once patients are placed on a ventilator.

    While SDD may reduce infections and prevent deaths, it has not been widely adopted as the evidence was not considered strong enough and there are widely held concerns about the potential risk of causing antibiotic resistance.

    To address this uncertainty, the Selective Decontamination of the Digestive tract in the Intensive Care Unit (SuDDICU) trial was designed to determine whether adding SDD to the usual care of ICU patients would reduce all-cause hospital mortality compared to usual care alone.

    The SuDDICU trial recruited 5,982 mechanically ventilated adults from 19 ICUs in Australia between April 2018 and May 2021. Each ICU delivered either SDD with usual care or usual care alone for 12 months and then crossed over to the other option for a second 12-month period.

    The study found that while SDD with standard care compared to standard care alone did not result in a statistically significant reduction in in-hospital mortality (27.0% vs 29.1% respectively), the range of values included a clinically important benefit.

    “Moreover, we saw that SDD was also associated with a significant reduction in new hospital-acquired infections and there were no adverse events related to the administration of SDD itself,” said Professor Myburgh.

    George Institute investigators combined the results with those of other major randomised clinical trials of SDD conducted over the last 20 years in a systematic review and meta-analysis, also being published in JAMA and presented at the conference by senior author, Associate Professor Anthony Delaney.

    “This review provides a high degree of certainty for clinicians to administer SDD to critically ill, mechanically ventilated patients in their ICUs to reduce the incidence of ventilator-associated pneumonia and the potential increased risk of death,” A/Prof Delaney said.

    Professor Myburgh added that SDD alongside other important strategies reinforces the importance of effective and safe preventive medicine in this vulnerable patient population.

    “We now plan to extend our trial to low and middle-income countries where mortality rates and the incidence of infections with antimicrobial resistant organisms are higher,” he said.

    Story Source:

    Materials provided by George Institute for Global Health. Note: Content may be edited for style and length.

    Journal Reference:

  • The SuDDICU Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group. Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation. JAMA, 2022; DOI: 10.1001/jama.2022.17927

    • George Institute for Global Health
    Microbiology

    A potential target for developing broad-spectrum antiviral therapies

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    Researchers have identified a promising strategy for development of broad-spectrum antiviral therapies that centers around promoting a strong immune response capable of stopping a number of viruses in their infectious tracks.

    Experiments in cell cultures and mice showed that blocking the function of a specific enzyme present in all cells triggers a powerful innate immune response, the body’s first line of defense against any foreign invader. When challenged by several types of viruses in the study, this response dramatically lowered replication of viral particles and protected mouse lungs from damage.

    There are still several avenues to explore, but the scientists say the finding could help change the approach to developing antiviral medications.

    “Typically, in antiviral development, the saying is, ‘one bug, one drug,'” said Jianrong Li, co-senior author of the study and a professor of virology in The Ohio State University Department of Veterinary Biosciences and Infectious Diseases Institute.

    “A drug that can stimulate the immune system to have broad antiviral activities would be very attractive — one drug against multiple bugs would be an ideal situation.”

    The study is published in the journal Proceedings of the National Academy of Sciences.

    This discovery was enabled in part by a technique the researchers used to map the precise location of an RNA modification they were studying, and to see which enzyme made the modification. The mapping led them to determine that this enzyme’s work happens not in viruses, but in mammal hosts that viruses want to infect.

    “If you can detect the modification, then you can study it and target it. But it took a while to figure this out — in the beginning of the pandemic, a lot of people, including our lab, were studying RNA modifications in hosts and viruses,” said co-senior author Chuan He, John T. Wilson Distinguished Service Professor of chemistry, biochemistry and molecular biology at the University of Chicago. “It turns out the key here is not a viral RNA modification, but a host RNA modification, and it triggers a host immune response.”

    Viruses tested against the immune response in this study included two that can cause severe respiratory infections in infants and the elderly, human respiratory syncytial virus and human metapneumovirus, as well as a mouse respiratory virus called Sendai virus, the vesicular stomatitis virus found in cattle and the herpes simplex virus, a DNA virus. Replication and gene expression of all of these viruses were significantly reduced when the enzyme was blocked, and the researchers said preliminary data from earlier studies in cell cultures suggested the SARS-CoV-2 virus could be similarly controlled by this antiviral strategy.

    The RNA modification itself, known as cytosine-5 methylation, or m5C, is actually what needs to be altered to trigger the immune system response. It is one of roughly 170 known chemical modifications on RNA molecules in living organisms that affect biological processes in a variety of ways.

    In lieu of targeting the modification, researchers were able to inhibit the function of a key enzyme in that process, called NSUN2, to stop the RNA change. Suppressing NSUN2 using gene knockdown techniques and experimental agents, they found, sets off a cascade of cell activities that leads to robust production of type 1 interferon, one of the most potent fighters in the innate antiviral response.

    “Amazingly, blockage of NSUN2 almost completely shuts down the replication of vesicular stomatitis virus, a model virus that normally kills the host cells within 24 hours and replicates to a very high titer, and strongly inhibits both RNA and DNA viruses,” said study co-first author Yuexiu Zhang, a PhD student in Li’s lab.

    It turns out that blocking NSUN2’s function in cells exposes RNA snippets that, despite belonging to the host, are seen as foreign invaders, which triggers the type 1 interferon production. Once available at this high level, the protein will stop the real threat: viruses trying to cause infection.

    The researchers verified this sequence of events during experiments in multiple types of cells and human lung models before observing the effects of blocking NSUN2 in mice.

    “We compared NSUN2-deficient mice with wild-type mice to see how the viruses act,” Li said. “Once we inhibited NSUN2, viral replication in the lung decreased and there was less pathology in the lung, and that correlated with enhanced type 1 interferon production.

    “This finding in mice and our other experiments proved that NSUN2 is a druggable target.”

    Next steps include developing a drug designed specifically to suppress NSUN2’s function, the researchers said.

    This study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute, where He is an investigator.

    Li-Sheng Zhang, a postdoctoral researcher in He’s lab, was co-first author of the work. Additional co-authors include Mijia Lu, Elizabeth Kairis, Valarmathy Murugaiah, Jiayu Xu, Rajni Kant Shukla, Xueya Liang, Estelle Cormet-Boyaka and Amit Sharma of Ohio State; Qing Dai and Zhongyu Zou of the University of Chicago; Phylip Chen and Mark Peeples of Nationwide Children’s Hospital; and Jianming Qiu of the University of Kansas Medical Center.

    He is a scientific founder of the drug-development company Accent Therapeutics, and Li and He have filed a provisional patent.

    Story Source:

    Materials provided by Ohio State University. Original written by Emily Caldwell. Note: Content may be edited for style and length.

    Journal Reference:

  • Yuexiu Zhang, Li-Sheng Zhang, Qing Dai, Phylip Chen, Mijia Lu, Elizabeth L. Kairis, Valarmathy Murugaiah, Jiayu Xu, Rajni Kant Shukla, Xueya Liang, Zhongyu Zou, Estelle Cormet-Boyaka, Jianming Qiu, Mark E. Peeples, Amit Sharma, Chuan He, Jianrong Li. 5-methylcytosine (m 5 C) RNA modification controls the innate immune response to virus infection by regulating type I interferons. Proceedings of the National Academy of Sciences, 2022; 119 (42) DOI: 10.1073/pnas.2123338119

    • Ohio State University
    Microbiology

    Clinical trial to evaluate antiviral drug for monkeypox begins in the Democratic Republic of the Congo

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    Reviewed by Emily Henderson, B.Sc.Oct 12 2022

    A clinical trial to evaluate the antiviral drug tecovirimat, also known as TPOXX, in adults and children with monkeypox has begun in the Democratic Republic of the Congo (DRC). The trial will evaluate the drug’s safety and its ability to mitigate monkeypox symptoms and prevent serious outcomes, including death. The National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health, and the DRC’s National Institute for Biomedical Research (INRB) are co-leading the trial as part of the government-to-government PALM partnership. Collaborating institutions include the U.S. Centers for Disease Control and Prevention (CDC), the Institute of Tropical Medicine Antwerp, the aid organization Alliance for International Medical Action (ALIMA) and the World Health Organization (WHO).

    TPOXX, made by the pharmaceutical company SIGA Technologies, Inc. (New York), is approved by the U.S. Food and Drug Administration for the treatment of smallpox. The drug impedes the spread of virus in the body by preventing virus particles from exiting human cells. The drug targets a protein that is found on both the virus that causes smallpox and the monkeypox virus.

    “Monkeypox has caused a high burden of disease and death in children and adults in the Democratic Republic of the Congo, and improved treatment options are urgently needed,” said NIAID Director Anthony S. Fauci, M.D. “This clinical trial will yield critical information about the safety and efficacy of tecovirimat for monkeypox. I want to thank our DRC scientific partners as well as the Congolese people for their continued collaboration in advancing this important clinical research.”

    Since the 1970s, monkeypox virus has caused sporadic cases and outbreaks, primarily in the rainforest areas of central Africa, and in west Africa. A multi-continent outbreak of monkeypox in areas where the disease is not endemic, including Europe and the United States, has been ongoing since May 2022 with the majority of cases occurring in men who have sex with men. The outbreak has prompted recent public health emergency declarations from the WHO and the U.S. Department of Health and Human Services. From Jan.1, 2022 to Oct. 5, 2022, the WHO has reported 68,900 confirmed cases and 25 deaths from 106 countries, areas and territories.

    According to the WHO, cases identified as part of the ongoing global outbreak are largely caused by monkeypox virus Clade IIb. Clade I, which is estimated to cause more severe disease and higher mortality than Clade IIa and Clade IIb, especially in children, is responsible for infections in the DRC. The Africa Centres for Disease Control and Prevention (Africa CDC) has reported 3,326 cases of monkeypox (165 confirmed; 3,161 suspected) and 120 deaths in the DRC from Jan. 1, 2022 to Sept. 21, 2022.

    People can become infected with monkeypox through contact with infected animals, such as rodents, or nonhuman primates or humans. The virus can transmit among humans by direct contact with skin lesions, body fluids, and respiratory droplets, including through intimate and sexual contact; and by indirect contact with contaminated clothing or bedding. Monkeypox can cause flu-like symptoms and painful skin lesions. Complications can include dehydration, bacterial infections, pneumonia, brain inflammation, sepsis, eye infections and death.

    The trial will enroll up to 450 adults and children with laboratory-confirmed monkeypox infection who weigh at least 3 kilograms (kg). Pregnant women are also eligible to enroll. The volunteer participants will be assigned at random to receive either oral tecovirimat or placebo capsules twice daily for 14 days, with the dose administered dependent on the participant’s weight. The trial is double-blinded, so participants and investigators do not know who will receive tecovirimat or placebo.

    All participants will stay at a hospital for at least 14 days where they will receive supportive care. Study clinicians will regularly monitor participants’ clinical status throughout the study, and participants will be asked to provide blood, throat swab, and skin lesion swab samples for laboratory evaluations. The study is primarily designed to compare the average time to healed skin lesions among those receiving tecovirimat versus those receiving placebo. Investigators will also gather data on multiple secondary objectives, including comparisons of how quickly participants test negative for monkeypox virus in the blood, overall severity and duration of disease, and mortality between groups.

    Participants will be discharged from the hospital once all lesions have scabbed over or flaked off, and after they test negative for monkeypox virus in the blood for two days in a row. They will be followed for at least 28 days and will be asked to return for an optional study visit after 58 days for additional clinical and laboratory tests. An independent Data and Safety Monitoring Board will monitor participant safety throughout the duration of the study.

    The trial is led by co-principal investigators Jean-Jacques Muyembe-Tamfum, M.D., Ph.D., director-general of INRB and professor of microbiology at Kinshasa University Medical School in Gombe, Kinshasa; and Placide Mbala, M.D., Ph.D., operations manager of the PALM project and head of the Epidemiology Department and the Pathogen Genomic Laboratory at INRB.

    “I am happy that monkeypox is no longer a neglected disease and that soon, thanks to this study, we will be able to prove that there is an effective treatment for this disease,” said Dr. Muyembe-Tamfum.

    For more information, please visit clinicaltrials.gov and search identifier NCT05559099. The trial timeline will depend on the pace of enrollment. A separate NIAID-supported trial of TPOXX is ongoing in the United States. For information about the U.S. trial, visit the AIDS Clinical Trials Group (ACTG) website and search TPOXX or study A5418.

    PALM is short for “Pamoja Tulinde Maisha” a Kiswahili phrase that translates to “together save lives.”  NIAID and the DRC Ministry of Health established the PALM clinical research partnership in response to the 2018 Ebola outbreak in Eastern DRC. The collaboration has continued as a multilateral clinical research program composed of NIAID, the DRC Ministry of Health, INRB and INRB’s partners. PALM’s first study was the randomized controlled trial of multiple therapeutics for Ebola virus disease, which supported the regulatory approvals of the NIAID-developed mAb114 (Ebanga) and REGN-EB3 (Inmazeb, developed by Regeneron) treatments.

    Source:

    National Institutes of Health