Putting some backbone into bacterial killers

Molecules need a bit of backbone in order to punch through bacterial membranes, say US chemists. The chemists developed a novel folded oligomer (foldamer) that is highly effective at puncturing bacteria and could form the basis for a novel class of antibiotics.

Puncturing bacterial membranes is a defensive strategy adopted by host defence peptides (HDPs), killing off the pathogens and protecting many animal species, including humans, against infection. HDPs are difficult to develop resistance against and there has been much interest in their antibacterial potential.

’Despite their promise, there has been little success in developing HDPs for clinical applications, due to their limited tissue distribution, lack of stability and expense of preparation,’ said William DeGrado, professor of biochemistry at the University of Pennsylvania. DeGrado and other researchers work on developing synthetic HDPs based on foldamers, but these often have complex structures and sometimes target both bacterial and mammalian cells.

Gregory Tew, a polymer scientist at the University of Massachusetts, used computational design methods to improve the antibacterial properties of one foldamer. This foldamer, which is based on a central 4,6-dicarboxy pyrimidine ring, was first developed by DeGrado’s team.

Tew’s team discovered that replacing two of the carbon atoms in 4,6-dicarboxy pyrimidine with nitrogen atoms greatly strengthened the molecule’s backbone and improved its antibacterial properties. This novel foldamer was a more effective and selective antibiotic than most other natural or synthetic HDPs.

’It is a stunning piece of work that is full of promise,’ DeGrado told Chemistry World, ’both from a fundamental as well as a practical perspective.’

Jon Evans