A Cell-Wall Building Protein Could Cause the Downfall of Bacteria
The shape, elongation, division and sporulation (SEDS) proteins are a large family of ubiquitous and essential transmembrane enzymes with critical roles in bacterial cell wall biology.
The exact function of SEDS proteins was for a long time poorly understood, but now, a recent research by a team at the Harvard Medical School has revealed how it could make for an uncompromisable Achilles heel of most bacteria.
The study has revealed that the prototypical SEDS family member RodA is a peptidoglycan polymerase—a role previously attributed exclusively to members of the penicillin-binding protein family. This discovery has thereby made RodA and other SEDS proteins promising targets for the development of next-generation antibiotics.
“Our latest findings reveal the molecular structure of RodA and identify targetable spots where new antibacterial drugs could bind and subvert its work,” said study senior investigator Andrew Kruse, associate professor of biological chemistry and molecular pharmacology at Harvard Medical School.
The researchers mapped RodA’s molecular structure and found that it included an unusual cavity on its outer edge. And where there’s a gap – in anything, really – sooner or later someone will find an object to fill it.
To
test the limits of RodA’s apparent weak spot, the scientists set up experiments using two species drawn from the two basic bacterial domains – gram-negative and gram-positive.In both cases, they found that making even small changes to the shape of the cavity caused the bacteria to distort, swell, and eventually burst. For drug developers, the result is potentially great news.
“What makes us excited is that this protein has a fairly discrete pocket that looks like it could be easily and effectively targeted with a drug that binds to it and interferes with the protein’s ability to do its job,” said study co-senior author David Rudner, professor of microbiology and immunobiology at Harvard Medical School.
“A chemical compound—an inhibitor—that binds to this pocket would interfere with the protein’s ability to synthesize and maintain the bacterial wall,” Rudner said. “That would, in essence, crack the wall, weaken the cell and set off a cascade that eventually causes it to die.”
Additionally, because the protein is highly conserved across all bacterial species, the discovery of an inhibiting compound means that, at least in theory, a drug could work against many kinds of harmful bacteria.
“This highlights the beauty of super-basic scientific discovery,” said co-investigator Thomas Bernhardt, professor of microbiology and immunobiology at Harvard Medical School. “You get to the most fundamental level of things that are found across all species, and when something works in one of them, chances are it will work across the board.”
The success of this “roundabout” approach, researchers said, circumvents a significant hurdle in field of structural biology and can open the doors toward defining the structures of many more newly discovered proteins.
“These insights underscore the importance of creative crosspollination among scientists from multiple disciplines and departments,” said study first author Megan Sjodt, a research fellow in biological chemistry and molecular pharmacology at Harvard Medical School. “We believe our results set the stage for subsequent work toward the discovery and optimization of new classes of antibiotics.”
