Antibiotics are indispensable to the modern health care system, assisting and complementing our immune systems. Over the past 10 years, the rapid emergence of bacteria strains that are resistant to multiple drugs has heightened the need to develop new classes of antibiotics. A particularly promising class of these new antibiotics are called antimicrobial peptides (AMPs).
Hundreds of AMPs of vertebrate and invertebrate origin have been discovered in the past decade, but they have existed since prehistoric times. Gene-encoded antimicrobial peptides are now well known to be a pervasive component of the immune defense system throughout the animal kingdom. They work by attacking the bacterial cell membrane. This process is called cell lysis. Formation of pores in the protective layer causes cell death by allowing the flow of ions and molecules into and out of the cell non-selectively. Most other antibiotics attack bacteria by attacking specific molecules that are part of the bacterial cellular machinery, against which bacteria can develop resistance. Yet bacteria have not been able to develop a resistance to AMPs that have existed for millennia. In order to develop resistance to AMPs, the bacterium must reengineer its outer membrane, a very difficult and complex proposition.
Unfortunately, most naturally occurring AMPs are toxic. They cause hemolysis, or the premature breakdown of blood cells, and are thus inappropriate for therapeutic purposes. The exact mechanism behind AMPs bringing about cell lysis, whether in blood cells or targeted microbial cells, is not yet understood. Hence, further efforts are needed to understand and engineer AMPs that are less toxic and have improved therapeutic qualities.
Yiannis Kaznessis, who leads one such research project at the University of Minnesota, is focusing on a class of AMPs called cathelicidins. He and his graduate student, Himanshu Khandelia, are trying to understand how these antimicrobial peptides work at the molecular level. They are using computational modeling on NCSA’s SGI Origin2000 and new IBM p690 supercomputing system known as Copper to quantify interactions with lipid molecules, which are an integral part of membranes in both pathogens and friendly cells. How exactly AMPs disrupt the membrane structure remains unclear. This lack of a molecular-level picture hampers the engineering of peptide antibiotics. However, the Kaznessis team's observations will help clarify this picture and enable the design of a novel class of antibiotics.
Access Online | Posted 9-9-2003