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  • richardmitnick 1:56 pm on September 6, 2018 Permalink | Reply
    Tags: Antibiotics, , , , ,   

    From ASCR Discovery: “Overcoming resistance” 

    From ASCR Discovery
    ASCR – Advancing Science Through Computing

    To revive antibiotics and devise new drug designs, Georgia Tech researchers team up with Oak Ridge’s Titan supercomputer.

    AcrAB:TolC in the cell envelope. There are six copies of AcrA (orange) bridging the gap between AcrB (blue) and TolC (yellow). Image courtesy of James Gumbart/Georgia Tech.

    Antibiotic resistance is a growing medical crisis, as disease-causing bacteria have developed properties that evade or overcome the toxic effects of many available drugs. More of these microbes are resistant to multiple medications, limiting physicians’ options to combat patients’ infections. As a result, a range of conditions – including pneumonia, bloodstream infections and gonorrhea – have become more dangerous and more expensive to treat, increasing healthcare costs by up to $20 billion annually.

    As researchers seek new antibiotics, they must overcome the mechanisms these microbes have evolved to survive. Most of today’s medications don’t work well against Gram-negative bacteria, which are difficult to penetrate because they are surrounded by two membranes with a cell wall sandwiched in between. (Gram-positive bacteria lack the outer membrane.) Gram-negative bacteria also deploy other defense systems: they assemble an assortment of membrane proteins into elaborate defensive structures known as efflux pumps that allow the cells to expel microbe-killing drugs before they work.

    Knocking out efflux pumps is a promising strategy both to create new drugs and bring old antibiotics back to life, says physicist James C. Gumbart of the Georgia Institute of Technology. But to target and neutralize these structures, researchers first must understand exactly how they function.

    That’s where simulations can help. Over the long term, Gumbart would like to model the molecular dynamics – how molecules in efflux pumps interact – with the goal of rendering these defenses harmless.

    As one step in that process, Gumbart and his colleagues have zeroed in on a critical component of efflux pumps: the adaptor protein AcrA, which links the efflux pump components on the inner membrane with those on the outer membrane. “We know from various structural data that AcrA is a key component of the pump, bridging the gap between AcrB and TolC,” two other vital membrane proteins. “Whether it has any role beyond a structural one, we don’t know for sure,” Gumbart says.

    To better study this protein, Gumbart and his team have used Titan, the Cray XK7 supercomputer at the Oak Ridge Leadership Computing Facility, a Department of Energy (DOE) user facility, to simulate the shape and related stability of AcrA as it interacts with other efflux pump components.

    ORNL Cray XK7 Titan Supercomputer

    An allocation of 38 million processor hours from DOE’s Innovative and Novel Computational Impact on Theory and Experiment (INCITE) program supports their work. The research also relies on NAMD, a molecular dynamics code developed by the National Institutes of Health Center for Macromolecular Modeling and Bioinformatics at the University of Illinois, Urbana-Champaign, to simulate large biomolecular systems like this one in parallel on large numbers of computer processor cores.

    To construct their simulations, the team took advantage of a newly developed model of both membranes and the cell wall of the Gram-negative bacterium E. coli in atomistic detail. “To understand the assembly process, we must consider the environment in which it happens, namely the periplasm, which is the space between membranes,” Gumbart says. “The periplasm includes a number of proteins as well as the cell wall, a thin mesh that gives bacteria shape and stability in a variety of environments.” The researchers placed AcrA within an efflux pump structure that included partner proteins AcrB, from the inner envelope, and TolC, from the outer envelope.

    These petascale simulations, running at one quadrillion mathematical calculations per second, create parallel versions of the motions and energies of these bacterial proteins and membranes. The individual simulations include proteins whose conformations – ways that the molecules can easily twist and reshape themselves – differ subtly. To optimize their results, the researchers can occasionally swap energetically favorable conformations between simulations, a technique called replica exchange. Using this strategy, the scientists can map the free energy of the system.

    The lowest-energy combinations of AcrA, AcrB and TolC reveal scenarios and protein arrangements that are most likely to occur within a bacterial cell. For example, it isn’t currently clear if AcrA adapts its shape before or after it initially interacts with AcrB, Gumbart says. “Our free-energy maps should help us to distinguish between these possibilities.”

    The team also is analyzing its data to seek energy maps that show AcrA conformations that interfere with pump assembly. “If we can stabilize these conformations, we can hopefully inhibit multidrug efflux,” Gumbart says. That information can guide the design of new, precisely targeted drug candidates called efflux pump inhibitors (EPIs). “The EPIs, in turn, will prevent the pump assembly or else block its function post-assembly.”

    Such simulations also can test the effects of EPIs that Gumbart’s collaborators already have designed, providing valuable information about which drug candidates might prove most effective and should be studied further.

    If successful, this strategy could revive some antibiotics that are no longer in use, Gumbart says, because researchers expect that combining them with an EPI could restore their potency.

    Gumbart and his team gathered a trove of data in just one year. “It would have taken at least four to five years to obtain using common supercomputing resources,” he says. Team members include Jerry Parks of Oak Ridge National Laboratory; Jerome Baudry of the University of Alabama, Huntsville; Helen Zgurskaya of the University of Oklahoma; University of Tennessee, Knoxville graduate student Adam Green; and Georgia Tech graduate student Anthony Hazel.

    A better understanding of efflux pump assembly and strategies for altering or blocking these structures could be useful for treating other diseases, too. For example, a different type of pump causes drug resistance in cancer cells, Gumbart says. “In fact, efflux systems are found in all domains in life.”

    Since completing the simulations this spring, Gumbart and his colleagues have been analyzing the resulting data to quantify the free energies, find patterns in the favored vs. disfavored conformations, and even determine why only some mutations affect pump assembly. More simulations will be needed to address related questions, but the current data still hold a number of secrets. Gumbart and his team will keep digging.

    See the full article here.


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    ASCRDiscovery is a publication of The U.S. Department of Energy

  • richardmitnick 1:45 pm on October 10, 2017 Permalink | Reply
    Tags: Antibiotics, Antibiotics spiked with quantum dots fought off bacteria as effectively as 1000 times as much antibiotic alone, , , , , , Various superbugs are evolving too rapidly to be counteracted by traditional drugs   

    From ScienceNews: “Superbugs may meet their match in these nanoparticles” 

    ScienceNews bloc

    Science News

    October 9, 2017
    Maria Temming

    ‘Quantum dots’ mess with bacteria’s defenses, allowing antibiotics to work.

    ARMED AND DANGEROUS By producing a chemical that makes bacteria more vulnerable to antibiotic attack, quantum dots could help reboot medications that have lost their edge against hard-to-kill microbes. Kateryna Kon/Shutterstock

    Antibiotics may have a new teammate in the fight against drug-resistant infections.

    Researchers have engineered nanoparticles to produce chemicals that render bacteria more vulnerable to antibiotics. These quantum dots, described online October 4 in Science Advances, could help combat pathogens that have developed resistance to antibiotics (SN: 10/15/16, p. 11).

    “Various superbugs are evolving too rapidly to be counteracted by traditional drugs,” says Zhengtao Deng, a chemist at Nanjing University in China not involved in the research. “Drug resistant infections will kill an extra 10 million people a year worldwide by 2050 unless action is taken.”

    In the study, antibiotics spiked with quantum dots fought off bacteria as effectively as 1,000 times as much antibiotic alone. That’s “really impressive,” says Chao Zhong, a materials scientist at ShanghaiTech University who was not involved in the study. “This is a really comprehensive study.”

    Quantum dots, previously investigated as a tool to trace drug delivery throughout the body or to take snapshots of cells, are made of semiconductors — the same kind of material in such electronics as laptops and cellphones (SN: 7/11/15, p. 22). The new quantum dots are tiny chunks of cadmium telluride just 3 nanometers across, or about as wide as a strand of DNA.

    When illuminated by a specific frequency of green light, the nanoparticles’ electrons can pop off and glom onto nearby oxygen molecules — which are dissolved in water throughout the body — to create a chemical called superoxide. When a bacterial cell absorbs this superoxide, it throws the microbe’s internal chemistry so off-balance that the pathogen can’t defend itself against antibiotics, explains study coauthor Anushree Chatterjee, a chemical engineer at the University of Colorado Boulder.

    Chatterjee and colleagues mixed various amounts of quantum dots into different concentrations of each of five antibiotics, and then added these concoctions to samples of five drug-resistant bacterial strains, such as Salmonella and methicillin-resistant Staphylococcus aureus, or MRSA. In more than 75 percent of 480 tests of different antibiotic combinations on different bacteria, the researchers found that lower doses of antibiotics were required to kill or curb the growth of bacteria when the medicine was combined with quantum dots.

    One limitation of this treatment is that the green light that activates the nanoparticles can shine through only a few millimeters of flesh, says coauthor Prashant Nagpal, a chemical engineer also at the University of Colorado Boulder. So these quantum dots could probably be used only to treat skin or accessible wound infections.

    The researchers are now designing nanoparticles that absorb infrared light, which can pass through the body. “That could be really effective in deep tissue and bone infections,” Nagpal says.

    See the full article here .

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  • richardmitnick 8:41 am on July 12, 2017 Permalink | Reply
    Tags: Antibiotics, , Customized antibiotics treatments now possible, , ,   

    From ISRAEL21c: “Customized antibiotics treatments now possible” 


    July 6, 2017
    No writer credit found

    Antibiotics image by The26January/Shutterstock.com

    A diagnostic system developed at the Technion-Israel Institute of Technology enables rapid and accurate customization of an antibiotic to a patient.

    If the system is commercialized, patients with life-threatening infections or in need of urgent treatment will enjoy faster diagnostics, earlier and more effective treatment of infectious bacteria and improved recovery times.

    The findings related to the new Technion diagnostic system were published recently in the Proceedings of the National Academy of Sciences (PNAS).

    Antibiotics are one of the most effective ways to treat bacterial infections. But widespread use of antibiotics accelerates the development of resistant bacterial strains.

    In fact, in June, the World Health Organization updated its Essential Medicines List with new advice on use of antibiotics.

    “The rise in antibiotic resistance stems from how we are using – and misusing – these medicines,” said Dr Suzanne Hill, director of Essential Medicines and Health Products. “The new WHO list should help health system planners and prescribers ensure people who need antibiotics have access to them, and ensure they get the right one, so that the problem of resistance doesn’t get worse.”

    In 2014, infections with antimicrobial resistance (AMR) claimed the lives of more than 700,000 people worldwide, in addition to a cumulative expenditure of $35 billion a year in the US alone, reports the Technion.

    According to established estimates, for every hour that effective antibiotic treatment is delayed, survival rates drop by about 7.6% for patients with septic shock. Therefore, in order not to leave the patient without adequate protection while awaiting the results, many doctors will prescribe an antibiotic with a broad spectrum of activity in large doses. This phenomenon facilitates the emergence of AMR and also affects the microbiota – the population of “good bacteria” found in the human body that protects it.

    “Every day, tens to hundreds of tests are carried out at every hospital in Israel to map the resistance levels of infectious bacteria from samples taken from patients. The problem is that this is a very long test, since it is based on sending the sample to the lab, growing a bacterial culture in a petri dish and analyzing the culture. This process requires relatively large sampling and usually takes a few days, in part because the workday at labs is limited to around eight hours,” said Technion doctoral student Jonathan Avesar, one of the researchers on the new system.

    “Our method, on the other hand, provides accurate results in a short time based on a much smaller sample. It is obvious that a faster response allows us to start treatment earlier and improve the speed of recovery.”

    Fast results

    The innovative system developed at the Technion, called the SNDA-AST, quickly analyzes bacteria isolated from patients with infections and assesses their level of resistance to specific antibiotics. This enables the healthcare team to choose the most effective antibiotic a day earlier than when using traditional methods.

    Technion researchers demonstrated the ability to test bacteria directly from patient urine samples, thus skipping the isolation step and potentially saving two days for patients with urinary-tract infections.

    They developed a chip with hundreds of nanoliter (1,000 times smaller than a milliliter) wells inside it, each containing a few bacteria and a specific antibiotic. Detection of the bacterial response is done using a fluorescent marker, image-processing tools and statistical analysis of the colors obtained from the bacteria in all the nanoliter wells.

    The study tested 12 bacteria-antibiotic combinations.

    “The use of the technology that we developed reduces the size of the required sample by several orders of magnitude, reduces the scanning time by around 50%, significantly reduces the lab space required for testing and reduces the cost per test,” said Avesar.

    The study was led by Prof. Shulamit Levenberg, dean of the Technion Faculty of Biomedical Engineering, and was carried out in her lab by Avesar, postdoctoral student Dekel Rosenfeld and doctoral student Tom Ben-Arye.

    Also contributing were Assistant Prof. Moran Bercovici of the Technion Faculty of Mechanical Engineering, doctoral student Marianna Truman-Rosentsvit and Dr. Yuval Geffen, head of the Microbiology Laboratory at Rambam Health Care Campus in Haifa. The study was funded by a KAMIN grant from the Israel Innovation Authority and the Israeli Centers of Research Excellence (I-CORE).

    See the full article here.

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    ISRAEL21c is a non-partisan, nonprofit organization and the publisher of an English-language online news magazine recognized as the single most diverse and reliable source of news and information about 21st century Israel.

    Our website offers a vast resource of more than 10,000 originally researched and produced articles, videos, images and blogs by some of Israel’s leading journalists, uncovering the country’s rich and diverse culture, innovative spirit, wide-ranging contributions to humanity, and democratic civil society.

    Every week we reach millions of people through our website, social media channels, and e-newsletter.

  • richardmitnick 2:48 pm on September 14, 2015 Permalink | Reply
    Tags: Antibiotics, , , Staph infection,   

    From Wash U: “Combo of 3 antibiotics can kill deadly staph infections​​​” 

    Wash U Bloc

    Washington University in St.Louis

    September 14, 2015
    Jim Dryden

    Using three antibiotic drugs thought to be useless against MRSA infection — piperacillin and tazobactam (bottle on left) and meropenem — Washington University researchers, led by Gautam Dantas, PhD, have killed the deadly staph infection in culture and in laboratory mice.
    Robert Boston

    Scanning electron micrograph of a human neutrophil ingesting MRSA

    Three antibiotics that, individually, are not effective against a drug-resistant staph infection can kill the deadly pathogen when combined as a trio, according to new research.

    The researchers, at Washington University School of Medicine in St. Louis, have killed the bug — <a href="http://“>methicillin-resistant Staphylococcus aureus (MRSA) — in test tubes and laboratory mice, and believe the same three-drug strategy may work in people.

    “MRSA infections kill 11,000 people each year in the United States, and the pathogen is considered one of the world’s worst drug-resistant microbes,” said principal investigator Gautam Dantas, PhD, an associate professor of pathology and immunology. “Using the drug combination to treat people has the potential to begin quickly because all three antibiotics are approved by the FDA.”

    The study is published online Sept. 14 in the journal Nature Chemical Biology.

    The three drugs — meropenem, piperacillin and tazobactam — are from a class of antibiotics called beta-lactams that has not been effective against MRSA for decades.​​​​​​​​​​​​​​

    Shown are clumps of MRSA bacteria magnified more than 2,300 times by an electron microscope.

    Working with collaborators in the microbiology laboratory at Barnes-Jewish Hospital​ in St. Louis, Dantas’ team tested and genetically analyzed 73 different variants of the MRSA microbe to represent a range of hospital-acquired and community-acquired forms of the pathogen. The researchers treated the various MRSA bugs with the three-drug combination and found that the treatments worked in every case.

    Then, in experiments conducted by collaborators at the University of Notre Dame, the team found that the drug combination cured MRSA-infected mice and was as effective against the pathogen as one of the strongest antibiotics on the market.

    “Without treatment, these MRSA-infected mice tend to live less than a day, but the three-drug combination cured the mice,” Dantas said. “After the treatment, the mice were thriving.”

    Dantas explained that the drugs, which attack the cell wall of bacteria, work in a synergistic manner, meaning they are more effective combined than each alone.

    The researchers also found that the drugs didn’t produce resistance in MRSA bacteria — an important finding since more and more bacteria are developing resistance to available drugs.

    “This three-drug combination appears to prevent MRSA from becoming resistant to it,” Dantas said. “We know all bacteria eventually develop resistance to antibiotics, but this trio buys us some time, potentially a significant amount of time.”

    Dantas’ team also is investigating other antibiotics thought to be ineffective against various bacterial pathogens to see if they, too, may work if used in combination with other drugs.

    “We started with MRSA because it’s such a difficult bug to treat,” he said. “But we are optimistic the same type of approach may work against other deadly pathogens, such as Pseudomonas and certain virulent forms of E. coli.”

    Funding for this research comes from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of General Medical Sciences, and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH). Additional funding comes from an NIH Director’s New Innovator Award and a Ruth Kirschstein National Research Service Award from NIH.

    See the full article here .

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    Wash U campus

    Washington University’s mission is to discover and disseminate knowledge, and protect the freedom of inquiry through research, teaching, and learning.

    Washington University creates an environment to encourage and support an ethos of wide-ranging exploration. Washington University’s faculty and staff strive to enhance the lives and livelihoods of students, the people of the greater St. Louis community, the country, and the world.

  • richardmitnick 9:13 am on April 9, 2015 Permalink | Reply
    Tags: Antibiotics, ,   

    From NOVA: “Quick Test That Measures a Patient’s Own Proteins Could Slash Antibiotic Overuse” 



    19 Mar 2015
    R.A. Becker

    If you’ve ever been prescribed antibiotics to fight the flu, you’ve experienced first-hand how difficult it is for doctors to distinguish between bacterial infections and viral infections (the flu is the latter). Oftentimes, doctors will prescribe antibiotics just in case it’s a bacterial infection so the patient will recover sooner. Early administration of antibiotics can halt bacterial infections before they spiral out of control, but the practice has led to the overuse of our most precious drugs.

    Fortunately, a team of researchers announced yesterday that they may have solved this problem in the form of a blood test. It works by detecting the proteins produced by a patient’s own body in response to infection to quickly determine whether they have been sickened by a bacterial strain or a virus. It returns a result within minutes rather than the hours or days required with typical clinical tests.

    The new test could lengthen the useful life of antibiotics such as clindamycin, one of the most essential drugs, according to the World Health Organization.

    Today’s tests aren’t just slow, they also require that the infectious agent has multiplied enough inside the patient’s body that the levels are high enough to be detected, and can misidentify the root cause when a person has concurrent infections. To overcome these hurdles, scientists from Israeli biotech company MeMed looked to the patient’s own body to see which molecules the immune system produces when fighting off different kinds of infections.

    The test performed well, properly identifying the type of infection most of the time. The researchers even report that it is more accurate than typical clinical diagnostics. Here’s Smitha Mundasad, reporting for BBC News on the new test:

    It relies on the fact that bacteria and viruses can trigger different protein pathways once they infect the body.

    A novel one, called TRAIL, was particularly high in viral infections and depleted during bacterial ones. They combined this with two other proteins – one is already used in routine practice.

    The rapid test could slow the rampant spread of antibiotic resistance in bacteria. Inappropriately prescribing antibiotics to to combat a virus like the flu or using too low of a dose of antibiotics encourages bacteria to evolve traits that protect them from commonly used drugs.

    Antibiotic misuse is not a small problem. The CDC estimates that nearly half of all antibiotics should never have been prescribed in the first place, and antibiotic resistant bacteria infect around 2 million people each year in the United States, killing over 23,000 of those infected.

    Virus expert Jonathan Ball from the University of Nottingham is cautiously optimistic, telling the BBC’s Mundasad that while MeMed’s new test might reduce inappropriate antibiotic use, “It will be important to see how it performs in the long term.

    See the full article here.

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    NOVA is the highest rated science series on television and the most watched documentary series on public television. It is also one of television’s most acclaimed series, having won every major television award, most of them many times over.

  • richardmitnick 6:29 pm on January 7, 2015 Permalink | Reply
    Tags: Antibiotics, , ,   

    From MIT Tech Review: “From a Pile of Dirt, Researchers Discover New Antibiotic” 

    MIT Technology Review
    M.I.T Technology Review

    January 7, 2015
    Karen Weintraub

    A plastic storage crate filled with backyard dirt might have yielded the most powerful antibiotic discovered in decades.

    Employing a novel microfluidic device to grow soil bacteria, researchers in Boston and Bonn, Germany, say they have identified a new type of antibiotic that kills the bacteria that cause pneumonia, staph, and blood infections.

    The antibiotic, named teixobactin, has yet to be tested in people. But it cured mice of these infections, and it is so different from current antibiotics that the scientists, who reported their findings today in the journal Nature, said they hoped germs might never become resistant to it.

    Others said resistance to any antibiotic is inevitable, but they called the discovery important nonetheless. “It brings back the notion that there are lots of unanticipated surprises still lurking in the soil,” says Gerald Fink, a microbiologist at the Whitehead Institute, part of MIT.

    Other important antibiotics, including tetracycline and streptomycin, were also discovered in soil bacteria. But starting in the 1960s, it looked as if the earth might not give up any more of its natural defenses. That is because most soil germs can’t be grown in the lab and studied.

    Scientists switched to other approaches, but very few new classes of antibiotics have been discovered. With antibiotic resistance increasingly common, last year the World Health Organization predicted that this “discovery void” could lead to a post-antibiotic era, in which minor injuries and common infections could become killers again.

    The researchers discovered teixobactin using a new technology for soil prospecting that was developed by Slava Epstein, a biologist at Northeastern University in Boston. He devised a two-inch-long microfluidic chip that acts as a portable diffusion chamber.

    The researchers diluted dirt, including some from their own backyards, to capture a single soil microbe in each of 306 tiny holes on the chip’s surface. They then put the chip in a tub of dirt, allowing the germs to remain in their natural environment.

    “Essentially, we’re tricking the bacteria,” says Kim Lewis, the director of the Antimicrobial Discovery Center at Northeastern University, who led the research.

    Lewis says his team was able to grow colonies of bacteria robust enough to be transferred to a petri dish, where they could be tested to see if they produced antibiotics. “Apparently the bottleneck in growing bacteria is to achieve that first colony,” says Lewis. “Once that happens, they become domesticated.”

    Only about 1 percent of soil bacteria have ever been cultured, according to the researchers.

    Teixobactin appears to kill bacteria by binding to a fat molecule that is a building block of their cell walls. That’s an unusual mechanism, says Tanja Schneider, a researcher at the University of Bonn who worked on the project. Bacteria might not easily develop resistance to it, if ever.

    Other scientists say it is unlikely any drug could outwit bacteria indefinitely. “There’s not one single example where resistance hasn’t occurred,” says Henry Chambers, director of clinical research services at the University of California, San Fransisco, and an expert on antimicrobial resistance with the Infectious Diseases Society of America.

    Still, if it proves safe to use in people, teixobactin could provide a fresh weapon to doctors. A study by the Pew Charitable Trusts in 2014 found that only 38 new antibiotics were in development by pharmaceutical companies, even though about 23,000 people die in the U.S. each year from drug-resistant bacteria.

    Teixobactin has been licensed to NovoBiotic Pharmaceuticals in Cambridge, Massachusetts, which collaborated on the research. Lewis says it will take about two years before the drug can be tested in volunteers.

    See the full article here.

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    The mission of MIT Technology Review is to equip its audiences with the intelligence to understand a world shaped by technology.

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