Solid state NMR is unlocking the secrets of compounds found in natural membranes from frogs' legs to human lungs that could lead to an entirely new class of antibiotic drugs. The compounds in question are antimicrobial peptides (AMPs) act as a first line chemical defence system in a huge range of organisms and could provide a novel approach to defeating drugs resistance in bacteria.

Ayyalusamy "Rams" Ramamoorthy of the University of Michigan turned up the AMPs at the recent Biophysical Society in Baltimore, Maryland (3rd March) explaining how all animals investigated so far, including humans, rely on these compounds to prevent bacterial invasion of skin, mucous membranes, and other surfaces. Some AMPs can be turned up to the proverbial "eleven" as they not only fight bacteria but can attack viruses, fungi and even cancer cells. Ramamoorthy explains that drugs designed to mimic their behaviour might have widespread medical applications.

One aspect of AMPs that has puzzled biomedical researchers until now, is the origin of the high specificity of these compounds. Exactly how do they attack pathogens without harming healthy cells.

"They're like smart bombs," Ramamoorthy says, "We'd like to exploit their properties to design super-smart bombs, but before we can do that, we need to understand how these AMP smart bombs interact with membranes to destroy bacteria. We need to know how they're shaped before, during and after the process of attaching to bacteria and how they attach."

Solid-state NMR spectroscopy has provided the team with a detailed view of AMPs in the environment of the cell membrane. AMPs make bacterial membranes permeable by forming pores through the membrane's phospholipid bilayer, the researchers explain. they have used ¹³C-and ¹⁵N-NMR of macroscopically aligned bilayer samples, to study the structural properties of AMPs as they act on model bilayers. "Solid-state NMR spectroscopy is used to construct a detailed image of a peptide or protein and to reveal how it sits in the cell membrane," Ramamoorthy adds. This has already provided clues as to what chemical modifications to make in order to develop synthetic AMPs that are effective against drug-resistant strains of bacteria.

"Our overall mission is to use the kind of basic physical data we obtain from NMR to help interpret biological functions," Ramamoorthy explains. He is working with collaborators in Canada, Japan, India and the US pharmaceutical companies Genaera Corporation and Eli Lilly & Co.

Related links:

• Ram's Lab Page
• Biophysical Society

Article by David Bradley