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Supercharged antibiotics could turn tide against superbugs

An old drug supercharged by University of Queensland researchers has emerged as a new antibiotic that could destroy some of the world’s most dangerous superbugs.

The supercharge technique, led by Dr Mark Blaskovich and Professor Matt Cooper from UQ’s Institute for Molecular Bioscience (IMB), potentially could revitalise other antibiotics.

Antibiotic-resistant bacteria — superbugs — cause 700,000 deaths worldwide each year, and a UK government review has predicted this could rise to 10 million by 2050.

Dr Blaskovich said the old drug, vancomycin, was still widely used to treat extremely dangerous bacterial infections, but bacteria were becoming increasingly resistant to it.

“The rise of vancomycin-resistant bacteria, and the number of patients dying from resistant infections that cannot be successfully treated, stimulated our team to look at ways to revitalise old antibiotics,” Dr Blaskovich said.

“We did this by modifying vancomycin’s membrane-binding properties to selectively bind to bacterial membranes rather than those of human cells, creating a series of supercharged vancomycin derivatives called vancapticins.”

The rebooted vancomycin has the potential to treat methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE).

Professor Cooper said pharmaceutical companies had departed the antibiotic discovery field because new antibiotics were difficult to find and were not as lucrative as cholesterol-lowering medications or cancer treatments.

“Hence many scientists are re-engineering existing drugs to overcome bacterial resistance, rather than searching for new drugs,” he said.

“Drug development is normally focused on improving binding to a biological target, and rarely focuses on assessing membrane-binding properties.

“This approach worked with the vancapticins, and the question now is whether it can be used to revitalise other antibiotics that have lost effectiveness against resistant bacteria.

“Given the alarming rise of multi-drug resistant bacteria and the length of time it takes to develop a new antibiotic, we need to look at any solution that could fix the antibiotic drug discovery pipeline now,” Professor Cooper said.

The research, published in the journal Nature Communications, was supported by the Wellcome Trust, the world’s largest biomedical charity, and Australia’s National Health and Medical Research Council.

Story Source:

Materials provided by University of QueenslandNote: Content may be edited for style and length.


Journal Reference:

  1. Mark A. T. Blaskovich, Karl A. Hansford, Yujing Gong, Mark S. Butler, Craig Muldoon, Johnny X. Huang, Soumya Ramu, Alberto B. Silva, Mu Cheng, Angela M. Kavanagh, Zyta Ziora, Rajaratnam Premraj, Fredrik Lindahl, Tanya A. Bradford, June C. Lee, Tomislav Karoli, Ruby Pelingon, David J. Edwards, Maite Amado, Alysha G. Elliott, Wanida Phetsang, Noor Huda Daud, Johan E. Deecke, Hanna E. Sidjabat, Sefetogi Ramaologa, Johannes Zuegg, Jason R. Betley, Andrew P. G. Beevers, Richard A. G. Smith, Jason A. Roberts, David L. Paterson, Matthew A. Cooper. Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteriaNature Communications, 2018; 9 (1) DOI: 10.1038/s41467-017-02123-w
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IN THE NEWS

The cambodian cure for resistant scabies mites

A member shares his story in how he was cured from resistant scabies mites in Cambodia. Where ivermectin and permethrin failed a local monk in a small town in Cambodia combated it with natural herbs and ancient remedies

www.humanparasites.org
Facebook group: Human Parasites Support Network

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IN THE NEWS

New Lyme disease tests could offer quicker, more accurate detection

New tests to detect early Lyme disease — which is increasing beyond the summer months -could replace existing tests that often do not clearly identify the infection before health problems occur.

In an analysis published on December 7 in Clinical Infectious Diseases, scientists from Rutgers University, Harvard University, Yale University, National Institute of Allergy and Infectious Diseases of the NIH and other academic centers, industry and public health agencies say new diagnostic methods offer a better chance for more accurate detection of the infection from the Lyme bacteria.

“New tests are at hand that offer more accurate, less ambiguous test results that can yield actionable results in a timely fashion,” said Steven Schutzer, a physician-scientist at Rutgers New Jersey Medical School and senior author. “Improved tests will allow for earlier diagnosis which should improve patient outcomes.”

Lyme disease is the most common tick-borne infection in North America and Europe. There are currently over 300,000 cases of Lyme disease annually in the United States alone and the disease is increasing and spreading into new regions. Lyme disease frequently, but not always, presents with a bull’s-eye rash. When the rash is absent, a laboratory test is needed.

The only FDA approved Lyme disease tests, based on technology developed more than two decades ago, rely on detecting antibodies that the body’s immune system makes in response to the disease. These antibody-based tests are the most commonly used tests for Lyme disease and are the current standard.

One problem, however, is that many people produce similar — called “cross-reactive” — antibodies in response to other bacteria not associated with Lyme disease, which causes confusing results and makes test accuracy more difficult.

“New tests are more exact and are not as susceptible to the same false-positive or false-negative results associated with current tests,” said Schutzer.

Schutzer and his colleagues say more accurate testing would help doctors decide when to prescribe the antibiotics used to clear the infection and help avoid severe long-term health problems. Antibody tests, can take three weeks or more for the antibody levels to reach a point where the tests can pick up a positive result.

Those involved in the paper joined forces after meeting at Cold Spring Harbor Laboratory’s Banbury Center, a nonprofit research institution in New York. The meeting organized and chaired by Schutzer and John A. Branda, assistant professor of pathology at Harvard Medical School, focused on current Lyme disease tests and new scientific advances made in increasing the accuracy of the diagnosis.

“This meeting and paper resulting from it are particularly significant,” said Jan Witkowski, professor in the Watson School of Biological Sciences at Cold Spring Harbor Laboratory who along with Nobel Laureate James Watson asked Schutzer to lead several symposia. “The participants noted that there are greatly improved diagnostic tests for Lyme disease that can be implemented now, and that the way is open to the development of further tests.”

Story Source:

Materials

provided by Rutgers University. Original written by Robin Lally.


Journal Reference:

  1. John A Branda, Barbara A Body, Jeff Boyle, Bernard M Branson, Raymond J Dattwyler, Erol Fikrig, Noel J Gerald, Maria Gomes-Solecki, Martin Kintrup, Michel Ledizet, Andrew E Levin, Michael Lewinski, Lance A Liotta, Adriana Marques, Paul S Mead, Emmanuel F Mongodin, Segaran Pillai, Prasad Rao, William H Robinson, Kristian M Roth, Martin E Schriefer, Thomas Slezak, Jessica Snyder, Allen C Steere, Jan Witkowski, Susan J Wong, Steven E Schutzer. Advances in Serodiagnostic Testing for Lyme Disease Are at HandClinical Infectious Diseases, 2017; DOI: 10.1093/cid/cix943
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IN THE NEWS

Possible new way to treat parasitic infections discovered

A chemical that suppresses the lethal form of a parasitic infection caused by roundworms that affects up to 100 million people and usually causes only mild symptoms has now been identified by researchers.

 

UT Southwestern Medical Center researchers have identified a chemical that suppresses the lethal form of a parasitic infection caused by roundworms that affects up to 100 million people and usually causes only mild symptoms.

“The approach we used could be applied generally to any nematode parasite, not just this one type,” said Dr. David Mangelsdorf, Chair of Pharmacology, an Investigator in the Howard Hughes Medical Institute (HHMI), and one of three corresponding authors of the study published in the Proceedings of the National Academy of Sciences. The study’s other corresponding authors are at two universities in Philadelphia.

“The plan is to develop better compounds that mimic the Δ7-dafachronic acid used in this study and eventually to treat the host to stop parasitic infection,” he added.

The Centers for Disease Control and Prevention (CDC) reports that the soil-dwelling Strongyloides stercoralis nematode, or roundworm, is the primary strongyloides species that infects humans. Experts estimate that between 30 million and 100 million people are infected worldwide, and most of them are unaware of it because their symptoms are so mild. The parasite can persist for decades in the body because of the nematode’s unique ability to reinfect the host, repeatedly going through the early stages of its life cycle. The nematode that causes the original infection exists in dirt on all continents except Antarctica, and it is most common in warmer regions, particularly remote rural areas in the tropics and subtropics where walking barefoot combined with poor sanitation leads to infection.

However, in people with compromised immune systems — such as those using long-term steroids for asthma, joint pain, or after an organ transplant — the mild form of the illness can progress to the potentially lethal form, a situation called hyperinfection. Studies indicate that mortality from untreated hyperinfection can be as high as 87 percent.

The World Health Organization reports that although the parasitic illness has almost disappeared in countries where sanitation has improved, children remain especially vulnerable in endemic regions due to their elevated contact with dirt. Further, the drug of choice, ivermectin, is unavailable in some affected countries.

“Ivermectin is used to treat the disease but is less effective in the lethal form of the infection,” said Dr. Mangelsdorf, a Professor of Pharmacology and Biochemistry. “We do not know exactly how the glucocorticoid [steroid] causes hyperinfection, but once it does, ivermectin is much less effective, prompting the search for new drugs. The new drug we used in our mouse model appears to be very effective,” he said.

To study the still unknown pathogenesis of the disease, the researchers developed a mouse model susceptible to the full range of infection by the human parasite. Because mice with intact immune systems are resistant to S. stercoralis infection, the researchers began with an immunocompromised strain of mice, and then exposed some to a synthetic steroid called methylprednisolone (MPA) that is commonly used to treat asthma in humans.

The mice were then exposed to the parasitic worms. Compared with untreated mice, those that received the steroid showed a tenfold increase in the number of parasitic female worms and a 50 percent increase in mortality, said Dr. Mangelsdorf, who holds both the Alfred G. Gilman Distinguished Chair in Pharmacology and the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology in Honor of Harold B. Crasilneck, Ph.D.

In addition, third-stage larvae — the life cycle stage in which the worms can initiate hyperinfection — were found in higher numbers in the steroid-treated versus untreated mice, he added.

“Strikingly, treatment with a steroid hormone called Δ7-dafachronic acid, a chemical that binds to a parasite nuclear receptor called Ss-DAF-12, significantly reduced the worm burden in MPA-treated mice,” Dr. Mangelsdorf said. The Ss-DAF-12 receptor corresponds to a similar receptor in the long-studied C. elegans worm.

Dr. Mangelsdorf and colleagues previously showed (PNAS, 2009) that the DAF-12 receptor pathway is found in many parasitic species. They also showed that activating the receptor with Δ7-dafachronic acid could override the parasite’s development and prevent S. stercoralis from becoming infectious.

“Overall, this latest study provides a useful mouse model for S. stercoralis autoinfection and opens the possibility of new chemotherapy for hyperinfection by targeting the parasite’s own steroid hormone mechanism,” Dr. Mangelsdorf said.

Story Source:

Materials

provided by UT Southwestern Medical Center.


Journal Reference:

  1. John B. Patton, Sandra Bonne-Année, Jessica Deckman, Jessica A. Hess, April Torigian, Thomas J. Nolan, Zhu Wang, Steven A. Kliewer, Amy C. Durham, James J. Lee, Mark L. Eberhard, David J. Mangelsdorf, James B. Lok, David Abraham. Methylprednisolone acetate induces, and Δ7-dafachronic acid suppresses,Strongyloides stercoralishyperinfection in NSG miceProceedings of the National Academy of Sciences, 2018; 201712235 DOI: 10.1073/pnas.1712235114
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