Proteins Previously Overlooked Are Major Players in Building Bacterial Cell Walls

A new discovery made by researchers at Harvard Medical School suggests that SED proteins, proteins that had previously been overlooked, have turned out to be “major players” in bacterial cell wall synthesis; almost all bacteria use these proteins in the construction and maintenance of their cells walls, according to a press release. Scientists feel that this discovery may incite the development of new antibiotics that will specifically target the cell wall in order to eliminate dangerous bacteria.

David Rudner, PhD, senior author of the paper and HMS professor of microbiology and immunobiology, said, “We know these proteins are a great target because they are enzymes we can inhibit from the outside of the cell.”

Thomas Bernhardt, PhD, the paper’s co-author and HMS professor of microbiology and immunobiology added, “Now we have a better handle on what these proteins do and how a potential drug might affect their activity.”

According to an article published in Microbiology and Molecular Biology Reviews, “The cell wall is the principle stress-bearing and shape-maintaining element in bacteria, and its integrity is of critical importance to cell viability.” In addition, the cell wall, composed of chains of sugars that are bound together by peptides, is responsible for protecting the cell from external assaults made by drugs, toxins, and viruses, according to the press release.

Previous to this discovery, penicillin-binding proteins, bacterial proteins that bind penicillin and other antibiotics, were thought to be the only key players in bacterial cell wall synthesis. Penicillin was first discovered by Alexander Fleming in September 1928 and further research suggested that the substance did not harm animals but was capable of killing disease-producing microbes, a finding that suggested that it could potentially be used for treatment purposes. In 1942, it was used for exactly that, but it was not yet fully understood by scientists how penicillin could be used to block the proteins that built bacterial cell walls until 1957. Research regarding Escherichia coli, conducted through the 1970s and the 1980s, “fleshed out the mechanism by which penicillin-binding proteins build the cell wall,” according to the press release.

Following this, a discovery made in 2003 showed that Bacillus subtilis, a bacterium, was able, even when penicillin-binding proteins were absent, to grow and synthesize its cell wall. This finding had been overlooked by many of researchers in the field, however, some found themselves tormented by the “missing polymerase,” or “moonlighting enzyme,” according to the press release.

Tsuyoshi Uehara, former HMS research fellow in the Bernhardt lab and co-author of the paper thought that SEDS proteins, proteins that account for the cell’s shape, elongation, division, and spore formation, might be responsible for the missing enzyme. According to the press release, Uehara hypothesized that the movement of the SED proteins around the bacterial cell’s circumference suggests that they might play a role in creating the wall, and if they are inactivated, they might influence the synthesis of the cell wall.

Alexander Meeske, HMS graduate student in the Rudner lab and the paper’s first author, tested that hypothesis, that SEDS proteins played a role in cell wall synthesis. Meeske removed all penicillin-binding proteins involved in polymerizing the cell wall, according to the press release. Even eithout the penicillin-binding proteins, SEDS proteins continued to move normally, which suggested that they might be the missing enzymes aforementioned that play a major role in bacterial cell wall synthesis.

This discovery was followed by additional genetic and biochemical experiments that confirmed that unlike what as previously thought, that penicillin-binding proteins were perhaps the only cell wall synthesizers, SEDS proteins are a second family of cell wall synthesizers. In addition, the scientists found that the two different families of cell wall synthesizers can work together to build a cell wall: penicillin-binding proteins move diffusely as they create small strands and SEDS proteins make “hoop-like structures” as they orbit the cell, according to the press release. However, how they work together is still unknown.

When speaking further on the new discovery, Bernhardt said, “For a long time in the field, it was thought that one set of enzymes worked in one set of complexes to build a wall. Now we have two sets of enzymes appearing to work in two different systems. Somehow they have to coordinate to build this netlike structure that maintains integrity and expands as cells grow and divide.”

Furthermore, the scientists found that SEDS proteins have proven to be even more common in bacteria than penicillin-binding proteins are. With this finding, researchers hope to develop a potential therapy that will specifically target SEDS proteins, and thus, eliminate various types of harmful bacteria.

Bernhardt said, “Even though the history goes all the way back to the 1920s with penicillin, there’s plenty to learn.”

Rudner added, “That’s what makes this so exciting. In this modern era of sequenced genomes, we’re still discovering new enzymes that work in this pathway.”