HCOM - Biochemistry
Academic Research Center 202d
Education: Ph.D. Brown University 1974
Research Interest: Role of peptide conformation in antimicrobial potency and selectivity
Since most living organisms are very similar at the molecular level, it is difficult to find substances that are lethal to certain organisms without being harmful to others. Antibiotics, such as penicillin, have revolutionized the practice of medicine over the past fifty years since they can kill bacteria without harming human cells. Unfortunately, many bacteria have developed resistant to penicillin and most other antibiotics. The widespread use of common antibiotics has increased the number of resistant organisms, posing a health risk and creating a challenge to develop novel agents to thwart virulent organisms.
Many animals can produce small antimicrobial peptides that serve as part of their natural defense system. One example is a family of peptides called magainins that is synthesized in frog skin in response to wounding. These peptides are lethal to a wide range of microorganisms, including Gram-positive and Gram-negative bacteria, fungi, parasites, and enveloped viruses because they induce leakage in the cell membrane. Some of these peptides may even be able to attack tumor cells. Two shortcomings of these natural compounds, however, are that (1) very high peptide concentrations are needed for antimicrobial efficacy and (2) the difference in toxicity (therapeutic index) between target and host cells is not sufficiently high for systemic use.
A common feature of these peptides is their capacity to form an amphipathic alpha-helix (with polar and nonpolar groups on opposite faces of the helix), a structural feature believed to be important in their function as antimicrobial agents. Numerous analogues with sequences derived from these peptides have been prepared and examined. In nearly all cases, the strategy employed in enhancing activity involved increasing the amphipathic alpha-helical character of the peptide.
We designed a new type of linear peptide that is structurally distinct from the natural defense peptides. These peptides have no potential to form an amphipathic alpha-helix, but can form a highly amphipathic beta-sheet. Our new peptides have high antimicrobial activity and are much more selective for bacterial membranes vs. mammalian membranes as compared to the natural peptide design. Ohio University recently filed a patent application for this new class of antimicrobial peptides.
Our initial NIH funding allowed us to study the role of peptide conformation in antimicrobial potency and selectivity. Until now, no one had attempted a comprehensive study of the structure-function relationships of families of closely related linear peptides with simple sequences that were designed to adopt different secondary structures. This approach revealed the importance of amphipathic character in determining antimicrobial activity and selectivity between bacterial and mammalian membranes.
Using the two families of peptides with varying capacity to form amphipathic alpha-helical and beta-sheet structures, we investigated the following areas: 1) the relationship of secondary structure and amphipathic character of the peptides to antimicrobial activity; 2) the amount of peptide that must bind to the membrane in order to induce leakage; and 3) the role of the membrane lipid composition in determining susceptibility to peptide-induced increase in permeability. These results were published recently in Antimicrobial Agents and Chemotherapy.
Recently we created a collection of new smaller linear amphipathic beta-sheet peptides with enhanced potency. We are examining whether these peptides work by the same mechanism as the larger antimicrobial peptides and whether they have potential for systemic use. In addition, antiviral activity and the ability to selectively kill transformed human cells at concentrations that are not toxic to normal cells are under investigation. Our ultimate goal is to design smaller, more effective antimicrobial peptides that will augment the arsenal of available antibiotics in order to keep pace with the ever-increasing threat posed by antibiotic-resistant bacteria and viruses. This project has been supported by the National Institute of Allergy and Infectious Diseases (NIAID) since 2000 and funding was renewed in 2006.