A team of researchers from the Rutgers New Jersey Medical School have found genetic foot prints of tuberculosis bacteria that are resistant to the commonly used anti-tubercular drugs. This could help scientists develop drugs to combat drug resistance in tuberculosis.
Tuberculosis of TB is still one of the largest killers among all infectious diseases says the Centre for Disease Prevention and Control (CDC). TB has killed 1.3 million people in 2017 says the CDC and the infection is found in one fourth of the global population. These numbers denote the path breaking development made by this study. Drug resistance TB is becoming a growing menace globally with most strains of the bacteria not responding to the commonly used anti-tubercular drugs.
Dr. Hassan Safi, assistant professor of medicine worked alongside Dr. David Alland, professor and chief of infectious disease in the department of medicine at Rutgers and others on this study. Their study titled, “Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance,” was published in the latest issue of the journal Proceedings of the National Academy of Sciences (PNAS).
Bacteria Mycobacterium tuberculosis, the causative agent of tuberculosis. Image Credit: Kateryna Kon / Shutterstock
The researchers reveal that they found certain reversible mutations in the glpK gene in the Mycobacterium tuberculosis bacilli that causes TB. This gene is one of the key players in the metabolic pathways of the bacteria. Once there is the mutation, the bacilli develops tolerance to the first line anti-tubercular drugs and becomes difficult to kill.
Dr. Alland said in a statement, “By discovering these mutants, we have pin-pointed a genetically tractable cause of drug tolerance, and as a result, we now have a unique opportunity to develop and test new treatments that are effective against drug tolerant organisms, which could lead to more rapid and effective therapies for tuberculosis.” The researchers explained that during an infection with TB, these drug tolerant bacilli tend to accumulate and after treatment has been started, they tend to multiply even more rapidly. They explain that treatment needs to be continued for at least 6 months in most cases because of this phenomenon of activation and multiplication of the tolerant bacteria when they are exposed to a shorter round of anti tubercular drugs.
The researchers further noted that when the drug treatment is stopped, the bacteria shows a reversal of the mutation of the gene. They explained that this reversal back to normalcy by the bacteria makes it difficult for the researchers to discover the reason behind development of the drug tolerance. To overcome this tolerance and emergence of drug resistance TB treatment has been often a six monthly affair. Globally this long duration of treatment has been one of the major hurdles in treating TB patients completely until they are free of the infection and are not at risk of transmitting the infection. Despite a long therapy, there are relapses seen among many individuals with TB. The researchers explain that 20 percent of the people with TB when treated for less than six months tend to get a relapse of their infection. The numbers reduce to 5 percent among those who complete their six monthly treatment schedule.
The researchers explained that being “drug susceptible” at the start of the therapy does not mean drug sensitivity at the middle or end of the therapy. Now they know that becoming drug tolerant could be possible with a mutation in the glpK gene. They explain that it maybe this reversible ability to develop a mutation and consequently tolerance to the drug that could lead to dormancy of the infection. TB bacilli are capable of lying dormant within the body for long stretches of time that may be months to years and thus may escape the body’s immune system. It was this phenomenon of dormancy followed by activation that was being studied by Dr. Alland and his research team when they found the secret behind drug tolerance.
The authors wrote, “As a genetically trackable cause of drug tolerance, M. tuberculosis glpK mutants provides a unique opportunity to study these phenomena at a cellular and mechanistic level. These mutants could also be used for developing drugs that target tolerant populations, leading to more rapid and effective tuberculosis treatments.”
Dr. Alland said, “Because of this study, we now have the ability to track and manipulate genetic mutations so that they have the same characteristics as drug tolerant cases of tuberculosis. That's never been done before. If we are going to defeat this disease, we need to find effective treatments for drug tolerant TB, and we need to do it now.” The authors wrote in conclusion, “Drugs effective against phase-variant M. tuberculosis may hasten TB treatment and improve cure rates.”
Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance Hassan Safi, Pooja Gopal, Subramanya Lingaraju, Shuyi Ma, Carly Levine, Veronique Dartois, Michelle Yee, Liping Li, Landry Blanc, Hsin-Pin Ho Liang, Seema Husain, Mainul Hoque, Patricia Soteropoulos, Tige Rustad, David R. Sherman, Thomas Dick, David Alland Proceedings of the National Academy of Sciences Sep 2019, 201907631; DOI: 10.1073/pnas.1907631116, https://www.pnas.org/content/early/2019/09/04/1907631116