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    Home > Medical News > Medical World News > New strategy to beat antibiotic resistance! Modular synthesis redesigns existing antibiotic molecules.

    New strategy to beat antibiotic resistance! Modular synthesis redesigns existing antibiotic molecules.

    • Last Update: 2020-10-25
    • Source: Internet
    • Author: User
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    Antibiotic resistance is one of the most pressing public health threats in the world.
    in the United States alone, tens of thousands of people die each year from drug-resistant strains of common bacteria such as Staphylococcus aureus and enterococcus, which can cause almost untreatable hospital infections.
    few new antibiotics have been developed to fight infections that have developed resistance to traditional antibiotics, and it could take decades to bring any new drug to market.
    now, in a new study, researchers at the University of California, San Francisco, are using a different approach to antibiotic resistance: redesigning existing antibiotic molecules to avoid bacterial resistance.
    They designed a group of molecular LEGO blocks that can be altered and combined to form larger molecules, and in this way they built the first "reconstruction" drugs they wanted, which were shelved before they were rebuilt because of antibiotic resistance.
    results were published online September 23, 2020 in the journal Nature under the title "Synthetic Group A streptogramin antibiotics that Vat resistance".
    images from Nature, 2020, doi:10.1038/s41586-020-2761-3.
    "Our goal is to revive drugs that have not reached their full potential, especially those that have been shown to be safe in humans," said Dr. Ian Seiple, co-author of the paper and an assistant professor in the Department of Pharmaceutical Chemistry at the University of California, San Francisco School of Pharmacy.
    we can do that, we don't need to keep coming up with new drugs that can beat drug-resistant bacteria.
    redesign of existing drugs could be an important tool in this study.
    study, Seiple and his co-author, Dr. James Fraser, used a class of antibiotics called streptogramin to confirm this approach.
    streptococcus is very effective against Staphylococcus ale infection, but recently the bacteria have evolved a clever drug resistance mechanism.
    streptococcus disrupts the work of bacterial kerucleosomes to make proteins that are not functional.
    However, bacteria that are resistant to streptococcus produce a protein called Virginiamycin acetyl transferase (Virginiamycin acetyltransferase, Vat): Vat recognizes this antibiotic when streptococcus enters bacterial cells.
    vat captures the antibiotic and chemically invalidates it, preventing it from binding to bacterial kerucleosomes.
    , like most other antibiotics, are derived from natural antibiotic compounds produced by other organisms (usually bacteria) and are adapted to optimize their performance in the human body.
    Seiple believes there must also be ways to make further changes to the drug molecule so that it can evade the capture of the Vat protein.
    Seiple builds new streptococcus from scratch.
    To make the build process easier, Qi Li, co-lead author and postdoctoral researcher at Seiple Labs, created seven molecular modules that can be adapted as needed to produce a series of streptococcus molecular variants.
    system allows us to manipulate these molecular modules in a way that is not possible in nature," Seiple said.
    this provides us with an effective way to redesign these molecules from scratch, and we have more freedom to creatively modify their structure.
    Seiple and Li have their molecular modules, the next step is to understand their chemical properties at the molecular level to better understand how to modify and assemble these molecular modules.
    , Seiple worked with Fraser, which specializes in creating visual models of biom molecules.
    Fraser said, "My lab's contribution is, 'Now that you've got seven blocks, which of them should we modify and how?'" To get the answer to this question, jenna Pellegrino, co-lead author of the paper and a graduate student with the Fraser team, used two complementary techniques--- cryogenic electrons and X-ray crystal diffraction to create three-dimensional images of the drug and its target bacterial RNA and its star Vat protein at near-atomic resolution.
    these models, Li, Pellegrino, Seiple, and Fraser can observe which parts of the streptococcus molecule are critical to the function of this antibiotic.
    then, Li is free to fiddle with the non-essential areas of the drug to find modifications that prevent Vat from interacting with the drug, while still allowing it to bind to the UC target and causing the bacteria to lose function.
    the researchers found that two of the seven molecular modules seemed to offer potentially interesting modified bits.
    they constructed streptococcus variants that adjusted these bits and found that they were active in dozens of pathogenic strains.
    they also tested the effects of their most promising candidate compound against streptococcus-resistant Staphylococcus acobacteria in infected mice, and found that it was more than 10 times more effective than other streptococcus antibiotics.
    Seiple points out that the knowledge gained through these cooperative experiments could be applied to retrofitting many other antibiotics.
    we understand the mechanism by which other types of antibiotics bind to the same targets, " he said.
    we have established a workflow for using chemical methods to overcome resistance to antibiotics that have not yet reached their therapeutic potential.
    Seiple will continue to optimize these synthetic streptococcus, and then hopes to move the research to the private sector, where it can further develop and test these redesigned antibiotics and conduct human trials.
    he and Fraser plan to continue working together to revive other antibiotics that have been shelved because of bacterial resistance, and to improve a suite of tools to help people stay ahead of the curve in bacterial evolution.
    is a never-ending bacterial arms race," fraser said.
    but by studying the structures involved before resistance is produced, we can understand what the underlying mechanisms of resistance will be.
    this new insight will serve as a guide for making antibiotics that bacteria can't resist.
    " Reference: 1. Qi Li et al. Synthetic group A streptogramin antibiotics that overcome Vat resistance. Nature, 2020, doi:10.1038/s41586-020-2761-3.2.Daniel J. Blair et al. Synthetic group A streptogramin antibiotics that overcome Vat resistance. Nature, 2020, doi: 10.1038/d41586-020-02565-1.3.Customizable synthetic antibiotic outmaneuvers resistant bacteria Original title: Nature paper details new strategies to fight antibiotic resistance! Redesign existing antibiotic molecules with modular synthesis This article is sourced from Bio Valley, for more information please download Bio Valley APP (
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