• Researchers identify rare genetic marker

    From ScienceDaily@1:317/3 to All on Mon May 9 22:30:42 2022
    Researchers identify rare genetic markers of drug-resistant tuberculosis


    Date:
    May 9, 2022
    Source:
    San Diego State University
    Summary:
    Researchers have identified rare genetic markers in M. tuberculosis
    that could improve early detection of drug-resistant strains of
    the disease, helping prevent their spread.



    FULL STORY ==========================================================================
    To many, tuberculosis (TB) may seem like a disease from a bygone era. But
    it still claims more than one million lives every year. And the problem
    is growing worse as Mycobacterium tuberculosis, the pathogen that causes
    TB, continues to evolve resistance to the antibiotics used to treat
    the disease.


    ==========================================================================
    Now, researchers at San Diego State University have identified rare
    genetic markers in M. tuberculosis that could improve early detection
    of drug-resistant strains of the disease, helping prevent their spread.

    Searching for elusive variants To test whether someone has a strain
    of TB that will no longer respond to standard treatment, clinicians
    culture samples of mucus from the respiratory tract and barrage them
    with antibiotics.

    "But because TB grows so slowly, that takes weeks," said San Diego
    State University professor of public health Faramarz Valafar. "In
    those weeks that patient is going around spreading TB that might be antibiotic-resistant." He says molecular diagnostic tools are much
    faster. These test for common genetic markers of drug -resistance and
    allow for more timely treatment. But TB strains with rare mechanisms of resistance still elude molecular detection.



    ========================================================================== "They don't have the common genetic markers, but they are resistant,"
    said Valafar. This leads clinicians to incorrectly conclude that standard
    TB drugs will kill the bacteria. "And so the patient is given the wrong medications and continues to infect others for weeks -- sometimes months
    -- before they realize that these drugs aren't working.So we really
    want to prevent that." Derek Conkle-Gutierrez, a doctoral student in
    Valafar's lab, led the search for rare genetic mutations associated with resistance. The researchers obtained samples of M. tuberculosis from seven different countries where antibiotic resistance is common. Culturing
    the samples revealed that some were indeed drug-resistant, even though molecular diagnostics had failed to catch them.

    "First we confirmed that they didn't have the known markers and then we
    started looking for what other mutations are showing up exclusively in
    these unexplained resistant isolates," said Conkle-Gutierrez.

    The researchers identified one set of rare genetic mutations that may help block the common TB drug kanamycin from interfering with the pathogen's
    ability to synthesize the proteins it needs, rendering it harmless to
    the pathogen.

    Another set of mutations may do the same for the TB drug capreomycin.

    The study is published in the journal Antimicrobial Agents and
    Chemotherapy.



    ========================================================================== "This manuscript identifies potential markers; confirmatory work for
    the selection of markers for the next generation of more comprehensive molecular diagnostic platforms lies ahead," said Valafar.

    He says given the evolution of antibiotic resistance, molecular
    diagnostics will need to be updated frequently and be tailored to
    different regions of the world where antibiotic resistance in TB is
    common. Conkle-Gutierrez agrees.

    "The practice of going in and really looking for these unexplained cases, bringing them in, sequencing them, is a large, expensive project, but it
    needs to be done in order to find these rare cases so that they don't
    slip through the cracks and spread, causing more antibiotic resistance
    that just goes undetected." As researchers learned during the 20th
    century, the widespread use of lifesaving antibiotics may have transformed medicine, but bacterial pathogens, like M. tuberculosis, quickly evolved resistance to them. That's because the strains of bacteria that survive
    the onslaught of these powerful drugs harbor mutations that allow them
    to persist and multiply in number. This is exacerbated by the use of antibiotics in livestock and for non-bacterial infections in humans,
    such as those caused by viruses.

    Tuberculosis is close to home It's estimated that about a quarter of the world's population is infected with TB, which has two phases: latent and active. Most people stay in the latent phase because the body's immune
    system keeps the bacterial load in check. They remain symptom-free and
    are not contagious. About 10% of those infections convert into active
    TB. Patients then experience symptoms and can spread the disease to
    others.

    "It is a very important public health concern for the United States
    as well," said Valafar, who says many people in this country have
    latent TB. "The fear is that other pulmonary infections like COVID could overwhelm the immune system and trigger TB to go into its active phase. If
    this happens, TB will become a bigger problem in the Western world as
    well. We have already seen this in HIV co-infections. Even though HIV is
    not a pulmonary disease, because it weakens the immune system, it leads
    to activation of TB. Most patients who have HIV die from TB and not HIV." Ultimately, an effective vaccine for TB is sorely needed. Until then,
    improving molecular diagnostics for the detection of antibiotic resistance
    is important for controlling morbidity. To this end, Valafar's lab has
    recently received a grant to directly sequence drug-resistant TB from
    infected lung tissue.

    "And that will really break through some barriers that the tuberculosis research community has been facing," he said.


    ========================================================================== Story Source: Materials provided by San_Diego_State_University. Original written by Susanne Clara Bard. Note: Content may be edited for style
    and length.


    ========================================================================== Journal Reference:
    1. Derek Conkle-Gutierrez, Calvin Kim, Sarah M. Ramirez-Busby,
    Samuel J.

    Modlin, Mikael Mansjo", Jim Werngren, Leen Rigouts, Sven E. Hoffner,
    Faramarz Valafar. Distribution of Common and Rare Genetic Markers of
    Second-Line-Injectable-Drug Resistance in Mycobacterium tuberculosis
    Revealed by a Genome-Wide Association Study. Antimicrobial Agents
    and Chemotherapy, 2022; DOI: 10.1128/aac.02075-21 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/05/220509100917.htm

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