The chink in the bacterial wall

If the strength of the whole is equal to a chain’s weakest link, or a wall’s most damaged brick, then it follows, by analogy at least, that the most vulnerable part of a bacterium is the dent in its chief constructor protein.

That is the assumption made by researchers from the Harvard Medical School in the US, who have identified a curious concavity on the outer surface of a critical protein, and found a way to exploit it.

“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,” explains David Rudner, co-author of a paper in the journal Nature.

To make their discovery, Rudner and colleagues built on some of their earlier work, which concerned a protein family known as SEDS. The acronym stands for “shape, elongation, division and sporulation”, and describes a group that is widespread in bacteria. Its members have roles, still in some cases poorly understood, in building cell walls.

Their very ubiquity, the Harvard researchers point out, make SEDS proteins attractive targets for antibiotic development.

The new work concerns one particular SEDS member, known as RodA. This protein knits together large sugar molecules and amino acid clusters to build cell walls – an essential component of any bacterium’s defence system.

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.

“A chemical compound – an inhibitor – that binds to this pocket would interfere with the protein’s ability to synthesise and maintain the bacterial wall,” explains study first author Megan Sjodt.

“That would, in essence, crack the wall, weaken the cell and set off a cascade that eventually causes it to die.”

Because RodA is widely conserved, as the jargon has it, it is present in pretty much all bacterial species, meaning that a specific inhibitor could be very widely deployed.

“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,” says co-author Thomas Bernhardt.

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