Fighting the protective barriers of bacteria
One of the challenges in treating infectious bacteria is finding agents that can penetrate the protective barriers, also known as biofilms, that the organisms develop.
Biofilms are layers of sugar, proteins and DNA that surround many types of bacteria, making them extremely resistant to treatment. They are linked to a variety of infections and can develop on medical devices such as catheters, artificial joint implants and prosthetic devices.
Meng-Lun Hsieh, a Michigan State University College of Osteopathic Medicine student and doctoral candidate in the Department of Biochemistry and Molecular Biology, recently received a two-year fellowship from the National Institutes of Health for her research in understanding the role that gene regulation plays in bacterial biofilm formation. The $80,000 grant will fund the remainder of her Ph.D. and clinical training while she completes her dissertation research.
“Basically, there are two ways to attack the problem of biofilms,” Hsieh said. “You can treat already formed biofilms, or you can try to prevent them from forming in the first place.”
Working with associate professor Christopher Waters and NIH senior investigator Deborah Hinton, Hsieh is taking the latter approach.
She discovered that V. cholerae, a life-threatening bacterium often found in developing countries, uses both an activator protein and signaling molecule, known as c-di-GMP, to turn on the genes that are responsible for biofilm formation.
Hsieh believes that if she can figure out the mechanism by which c-di-GMP activates biofilm genes, she might be able to interrupt it and prevent biofilm formation.
To accomplish that, she is using several genetic and biochemical tools, as well as 3D-computer modeling to construct a molecular map of how the protein interacts with its DNA and how it interacts with other proteins.
“It's similar to playing with Legos or Tetris; We look at how each piece fits into a specific pocket or how they stack up on top of each other,” Hsieh said. “By understanding this, we can ultimately design new compounds that prevent these pieces from fitting together.”
Hsieh hopes that her work will provide the foundation needed for engineering new antimicrobials against V. cholerae and other bacteria that cause hospital-acquired and biofilm-based infections, a major problem in the United States and other developed countries.
She appreciates the interdisciplinary support she’s received from Hinton and Waters.
“I'm really fortunate to be mentored by two experts in the two very different yet complementary fields of biochemistry and microbial genetics,” Hsieh said. “I think that’s rare for a student and I'm so grateful to both Debbie and Chris. None of this would be possible without their help and training.”
Upon completion of her degrees, Hsieh plans to pursue a residency in internal medicine and then a fellowship in infectious disease.