Genetic mutations enable efficient evolution

Mycobacterium tuberculosis cells

image: Mycobacterium tuberculosis cells in a biofilm
vision Lake

Credit: John Kernien (CC BY 4.0)

Researchers have identified how the bacteria that causes tuberculosis (TB) can evolve rapidly in response to new environments, according to a study published today in eLife.

As with other types of bacteria, Mycobacterium tuberculosis M. tuberculosis) is able to form complex structures called biofilms, which allow bacterial cells to resist stressors such as antibiotics and immune cells. For this study, the research team measured populations of M. tuberculosis in the lab and found that it could form thick biofilms due to mutations in genetic regions that cause multiple changes to happen at once. These findings could contribute to the development of antibiotics that target biofilm growth.

As the second leading cause of death from infectious diseases worldwide, TB represents a major threat to public health and there is an urgent need for new strategies to diagnose, treat and control the infection.

“TB remains a challenging infection to treat because of the bacteria’s ability to persist in the face of antibiotics and immune pressures, and to acquire new drug resistance,” explains Madison Youngblom, graduate student in senior author Caitlin Pepperell’s lab, University of Wisconsin-Madison, USA, and co-first author of the study alongside Tracy Smith, New York Genome Center, New York City, USA. “To better treat and control TB, we need to understand the sources of the bacteria’s robustness and identify its vulnerabilities. We wanted to learn more about how it is able to form biofilms by discovering the genes and genetic regions involved in biofilm growth, as well as how the bacterium evolves in response to changes in its environment.”

To do this, the team used experimental evolution of M. tuberculosis – a powerful tool for uncovering the bacteria’s strengths and vulnerabilities, which has led to important insights into the fundamental processes that drive its adaptation. They evolved six closely related M. tuberculosis strains under selective pressure to grow as a biofilm. At regular intervals, they photographed the biofilm and described its growth according to four criteria: how much liquid surface covered the biofilm, its adherence to and growth along the sides of the shell, how thick the biofilm grew, and the continuity of growth (compared to discontinuous growth sites). .

Their work showed that each species could quickly adapt to environmental pressures, with the growth of a thicker and thus more robust biofilm. The genetic regions that mutated during the experiment and caused this biofilm growth were mostly regulators such as regX3, phoP, embR and Rv2488c. “These regulators regulate the activity of multiple genes, meaning a single mutation can cause many changes at once,” explains Youngblom. “This is an efficient process that we observed when we looked at the different characteristics of the bacteria, such as their cell size and growth rate.”

In addition, the team found evidence suggesting that the genetic background of the parental strain of M. tuberculosis had an impact on the enhanced growth of the biofilms. This means that interactions between genetic factors may play an important role in the adaptation of the M. tuberculosis to changing environments.

“Bacteria are amenable to growth as biofilms in many contexts, including the infection of humans and other hosts, and during colonization of natural and built environments,” said senior author Caitlin Pepperell, principal investigator at the University of Wisconsin-Madison. “In a medical context, the insights from our work can be used to investigate potential new antibiotics that can better attack bacteria that grow in this way. We envision that such biofilm-targeted therapies for tuberculosis are likely to complement conventional therapy to help shorten and simplify current treatment strategies.”

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