MSGID: 1:317/3 6279eabb   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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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