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Fighting Antibiotic Resistance

Today, antibiotics are under siege. Bacteria and other organisms, many displaying multi-drug resistance, are rapidly gaining ground. This poses one of the most serious challenges for medical science. As IIT Coleman Faculty Scholar and Assistant Professor of Physics David Gidalevitz points out, "Bacteria only need to undergo a slight mutation to make traditional antibiotics ineffective."

Many antibiotic drugs act by attaching to specific cell-surface receptors. When a bacterium mutates, it changes these binding sites so that the antibiotic either cannot attach, or binds to the membrane but loses its bactericidal effect. Gidalevitz believes a unique class of compounds known as antimicrobial peptides (also known as host defense peptides) may help humanity out of its antibacterial rut.

Antimicrobial peptides, or AMPs, occur naturally in organisms ranging from microbes to mammals. In humans, AMPs are part of our innate immune response—the first line of defense against infection. As Gidalevitz explains, these peptide defenders have some remarkable qualities. They can target an extremely wide range of pathogens, including two broad categories of bacteria (known as either Gram positive or Gram negative, based on their staining properties), as well as some viruses, protozoa, tumors, and even fungi. More importantly, AMPs are able to hunt and kill prokaryotic cells like bacteria while leaving our eukaryotic cells—the healthy cells in our bodies—undisturbed.

Gidalevitz's work involves the construction of membrane mimics, manmade nanostructures imitative of natural cell walls. He uses these mimics to better understand the precise mechanisms that allow AMPs to recognize and disrupt bacterial cell membranes, despite their structural variation. Although some experimental drugs composed of naturally occurring AMPs have been attempted, such compounds are quickly recognized by proteases in the body and destroyed before they are able to act. On the other hand, ampetoids—mimics of natural AMPs—are different. "Antimicrobial peptide mimics won't interfere with general biological systems," Gidalevitz says. "They're not recognized as such."

How do AMPs target bacterial cells for destruction? Part of the trick occurs through recognition of the lipid matrix of the bacterial cell wall, which carries an electrically negative charge (unlike eukaryotic cell walls which are electrically neutral). Generally, the kinds of mutations bacteria undergo in order to outwit traditional antibiotics can't save them from a frontal assault on the membrane chemistry by an antimicrobial peptide. Because of this, AMPs offer an attractive weapon in the pitched battle against resistant pathogens. To study the structure of membrane mimics and their interactions with AMPs, Gidalevitz takes a new approach, using sensitive technologies including synchrotron-grazing incidence X-ray diffraction and X-ray reflexivity, in collaboration with Argonne National Laboratory. "To investigate the action of the peptides and membrane mimics with these techniques is fairly novel," Gidalevitz notes. "These are definitely not tools used by a majority of biologists." Unlike natural cell walls, which are composed of a lipid bilayer, Gidalevitz's membrane mimics are monolayer structures applied to an aqueous surface in which natural AMPs are dissolved. The AMPs themselves are supplied by Gidalevitz's collaborators, including Annelise Barron of Standford University.

A $1.3 million National Institutes of Health grant will help Gidalevitz pursue this research for the next three years, though there is so much to learn about the subtleties of these powerful compounds, and their potential benefits so great, that he expects his work will likely continue long thereafter. Research into membrane dynamics and AMP mechanisms of action bring promise for the development of an entirely new class of peptide antibiotics, which will target pathogenic invaders and circumvent antibacterial resistance.

June 2, 2010 reprinted from IIT Magazine, Fall 2009