Bacteria can be hardy little creatures, thanks mostly to their strong cell walls that can protect them against drugs, viruses and other dangers. Finding ways to disarm these defenses is a key component of antibiotics, and now researchers at Harvard Medical School have identified a structural weakness that seems to be built into a range of bacterial species, potentially paving the way for a new class of widely-effective antibacterial drugs.
The new study builds on previous research into a protein named RodA. While the protein itself has long been known, in 2016 the Harvard team was the first to discover that it builds the protective cell walls of bacteria out of sugar molecules and amino acids. Since RodA belongs to the SEDS family of proteins, which is common to almost all bacteria, the team realized it was the perfect target for a far-reaching antibiotic. And on closer examination of RodA, the researchers spotted a vulnerable looking cavity on the outer surface of the protein.
"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," says David Rudner, co-senior author of the study.
To test whether this cavity was the Achilles' heel they were looking for, the scientists altered the structure of the protein in two species of bacteria, E. coli and Bacillus subtilis. These two were chosen because they're well understood and represent the two broad classes of disease-causing bacteria, gram-positive and gram-negative.
The team found that even small changes to the structure of the cavity caused the protein to malfunction, which in turn led the bacteria to swell up and burst. That suggests that a drug designed to trigger the same reaction would be an effective antibiotic.
"A chemical compound – an inhibitor – that binds to this pocket would interfere with the protein's ability to synthesize and maintain the bacterial wall," says Rudner. "That would, in essence, crack the wall, weaken the cell and set off a cascade that eventually causes it to die."
Better yet, because the SEDS family is so common, potential future drugs could be effective against a wide range of bacterial species.
"This highlights the beauty of super-basic scientific discovery," says Thomas Bernhardt, co-investigator on the study. "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 research was published in the journal Nature.
Source: Harvard Medical School
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