NMR Spectroscopy Reveals Bacterial-Fighting Properties of Natural Antibiotics

Frog skins and human lungs are being utilized to develop new antibiotics, and a technique called solid-state nuclear magnetic resonance (NMR) spectroscopy is providing insights into the properties of these natural peptide bacterial fighters.

Dr. Ayyalusamy Ramamoorthy and colleagues, from the University of Michigan (Ann Arbor, USA), are utilizing solid-state NMR to examine the germ-killing characteristics of natural antibiotics called antimicrobial peptides (AMPs), which are produced by nearly all animals, from insects to frogs to humans. AMPs are the immune system's early line of defense, fighting microbes at the first places they try to penetrate: skin, mucous membranes, and other surfaces. They are profusely produced in injured or infected frog skins, for instance, and the linings of the human respiratory and gastrointestinal tracts produce the short proteins in response to invading pathogens.

In addition to fighting bacteria, AMPs attack viruses, fungi and even cancer cells, so drugs designed to mimic them could have widespread medical applications, according to Dr. Ramamoorthy, who is an associate professor of chemistry and an associate research scientist in the biophysics research division. Whereas researchers have identified hundreds of AMPs recently, they still have not determined how precisely the peptides kill bacteria and other microbes. Unlike traditional antibiotics, which characteristically suppress specific bacterial proteins, AMPs get quite physical with invaders, punching holes into their membranes. But they are only selectively aggressive, targeting microbes but leaving healthy host cells alone.

"They're like smart bombs,” Dr. Ramamoorthy said. "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 is an ideal tool for answering such questions because it provides atom-level details of the molecule's structure in the complicated and challenging cell membrane environment, according to Dr. Ramamoorthy. "Just as an MRI [magnetic resonance imaging] produces a detailed image of our internal organs, 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,” providing insights for modifications that might make synthetic AMPs even more effective in overcoming ever-increasing bacterial resistance. For instance, rearranging parts of the molecule might make it fit into the membrane better, resulting in greater effectiveness with smaller amounts of AMP.

"Our overall mission is to use the kind of basic physical data we obtain from solid-state NMR spectroscopy to help interpret biological functions,” Dr. Ramamoorthy said. The study is highly interdisciplinary, involving not only Dr. Ramamoorthy's lab and several other groups in the chemistry department, but also researchers from the college of engineering, the school of dentistry, the Medical School, and the biophysics research division, as well as collaborators in Canada, Japan, India, and the U.S. pharmaceutical companies Genaera Corp. (Philadelphia, PA, USA) and Eli Lilly and Company (Indianapolis, IN, USA).

According to Dr. Ramamoorthy, this area of research will grow considerably at U-M from implementing plans to set up a high magnetic field solid-state NMR spectrometer facility. Dr. Ramamoorthy presented this group's findings on March 3, 2007 at the annual meeting of the Biophysical Society held in Baltimore, MD, USA.


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