Tien Nguyen, a fifth-year MCO graduate student, has received an NIH F31 fellowship to investigate how bacteria coordinate the final stages of cell division, research that could uncover new vulnerabilities for future antibiotics.
Nguyen conducts research in the laboratory of Thomas Bernhardt at Harvard Medical School. The fellowship provides three years of support for Nguyen’s research on cell division in Escherichia coli, an important model for understanding Gram-negative bacteria, a group that includes pathogens such as Salmonella.
“A lot of what we can do in E. coli can be translated over to other bacteria,” Nguyen said.
For a bacterial cell to divide successfully, it must precisely coordinate the construction and remodeling of its cell envelope. In Gram-negative bacteria, that envelope includes inner and outer membranes separated by a thin peptidoglycan cell wall. As one cell becomes two, all of these layers must constrict together while new cell-wall material is built.
Scientists have identified many of the proteins involved in this process. Now, Nguyen said, an important challenge is understanding how their activities are coordinated.
“The past few decades of microbiology research have really uncovered the key players of how division works,” Nguyen said. “What the field has moved towards now is understanding how all these players work in concert together to complete this really complicated process, and how it’s all tightly regulated and coordinated.”
Nguyen studies a critical step near the end of division, when the two emerging daughter cells must separate. Enzymes called amidases precisely cut the peptidoglycan cell wall the cells still share, allowing them to pull apart without compromising their newly formed cell envelopes.
That process requires tight control. Too little cleavage can interfere with cell separation, while uncontrolled cleavage could damage the daughter cells and cause them to lyse.
“You don’t want that separation to be so strong because you would actually damage the two daughter cells,” Nguyen said. “It has to be regulated in a very coordinated manner. At a high level, cell division is a delicate balance between cell wall synthesis and hydrolysis. Disruption of either is detrimental to the cell.”
Nguyen’s fellowship project focuses on NlpD, a protein that activates these cell-wall-cutting enzymes but whose own regulation remains poorly understood. Preliminary work points to FtsN, an essential cell division protein involved in peptidoglycan synthesis, as a potential regulator of NlpD.
Nguyen found that producing extra FtsN could suppress the lethal effects of misregulated forms of NlpD. Computational modeling and biochemical experiments also suggest that FtsN may interact with NlpD in a way that restrains its ability to activate amidases. This reveals a novel regulatory role for FtsN and places it as a critical factor that balances cell wall synthesis and cleavage.
“Tien has done an excellent job identifying a new role for a key division protein in coordinating cell wall synthesis and its remodeling,” Bernhardt said. “I am looking forward to seeing where he takes the project and am excited that he was able to secure funding to help support the work.”
With support from the fellowship, Nguyen will investigate how this potential interaction controls peptidoglycan cleavage during cell division and look for additional mechanisms that regulate NlpD.
Because cell division is essential for bacterial survival—and is already targeted by many effective antibiotics—uncovering additional control points could ultimately identify new opportunities for antibiotic development.
The fellowship will also support Nguyen’s scientific training toward a long-term goal of becoming an independent investigator.
