Protein in an envelope: spilling a Gram-negative bacterium’s secrets
Researchers have determined a protein’s essential role in bacterial envelope structure and function, which could inspire a search for better antibiotics.
Researchers at Johns Hopkins University (MD, USA) have discovered a protein’s essential role in producing a sugar molecule key to an environmental bacterium’s envelope shape. Leveraging what they’ve learned from their study, the researchers believe that this information could propel the search for new and improved antibiotics that target proteins involved in sugar synthesis for envelope maintenance and structure.
When studying bacteria from lakes and soil, researchers often come across Caulobacter crescentus, a Gram-negative aquatic bacterium that has a dimorphic life cycle and thrives in nutrient-poor environments. Although not generally thought of as a disease-causing bacterium, C. crescentus contains osmoregulated periplasmic glucans (OPGs) in its cell envelope, which are known to play a role in antibiotic resistance.
OPGs – glucose-containing molecules that fill up any spaces in the protective envelope – have different structures depending on the bacterial species and are found abundantly in Gram-negative bacteria, which are characterized by their double membrane. The researchers set out to learn more about these OPGs and their potential role in disease-causing bacteria, hoping to inform new drug discovery efforts targeting the production of these sugar molecules in species like Brucella, Pseudomonas, Salmonella and E. coli.
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Using an inducible promoter, the researchers reduced the presence of the OpgH protein, an enzyme involved in OPG production. They did this to observe how it would affect C. crescentus’ shape and how its loss would affect a pathway involved in identifying and repairing the cell envelope, called CenKR. They also manipulated CenR protein production, hyperactivating the CenKR pathway responsible for regulating cell shape. Following the researchers’ manipulation of the cells, they were placed on a gel pad to keep them stationary. Using a specialized microscope, the researchers then observed the cells.
They found that the cells became misshapen after reducing OpgH enzyme and that OPG production was halted. Interestingly, they observed the same cellular reaction when CenR was overexpressed. “Then we also looked at where some of the molecular players that helped to grow the cell and keep the shape of the cell were located,” Erin Goley, senior author of the study, remarked. “The molecular players were not in the correct locations, suggesting that OpgH and CenR are integral to maintaining the cell’s shape.” Once the cells lost their shape, they all burst open and died, a finding that could contribute to drug development strategies.
The researchers recognize that while this study highlights the role of OPGs in C. crescentus’ envelope and how disruption of OPG production or hyperactivity of the CenKR regulatory pathway impacts this bacterium’s cell shape, further research is needed to understand how OPG is implicated in other Gram-negative bacterial species.
“In the next phase of research, we hope to investigate all of the enzymes that make, decorate and break down these molecules [OPGs] — so we can get a full picture of their metabolism and how they maintain the cell envelope,” Goley concluded. “Once we uncover how these enzymes function, that’s great, because those are things drugs can target.”
