Oct. 24, 2000 Insects dominate the animal kingdom, both in terms of numbers and variety. One reason for their success is their remarkably swift and effective system of defense against infections, which differs dramatically from the immune systems of higher-order animals, including humans. Key to the insect immune system is an array of small antimicrobial peptide molecules. Most act, in essence, by latching on to the outer or inner membranes of bacteria and punching holes in the membranes, thereby killing the bacteria.
Now, in a new study, scientists at The Wistar Institute have identified an intracellular target for one of these antimicrobial molecules first isolated from a European sap-sucking insect. The molecule itself is currently being evaluated for its potential as an antibiotic in mammals, including humans. Knowledge of the receptor, however, may make it possible to develop an entirely new class of antibiotics, each rationally designed to fight a specific disease-causing bacterium or fungus. The new findings were published electronically on October 21 in the journal Biochemistry.
"Insects often live in hostile environments, and they are not very long-lived," says Wistar associate professor Laszlo Otvos Jr., Ph.D., lead author on the study. "So they need a rapid way to kill bacteria. In earlier work, we and others discovered several powerful antibiotic molecules used by flies, bees, and other insects to defend themselves against infection. In the current study, we identified the receptor for one of these molecules, which is potentially much more significant. With knowledge of the receptor, the doors are open to developing strain-specific antibiotics."
The new receptor is a heat shock protein referred to as DnaK. Heat shock proteins, in both bacteria and animals, play an all-important role during infections that produce fevers. Fevers cause the proteins that make up all cells to become misshapen, in some cases destroying their ability to do the work for which they were designed. Heat shock proteins help repair the problems, correcting the shapes of the proteins and restoring them to functionality.
The mechanism by which the sap-sucking insect's antimicrobial molecule kills bacteria, then, is to disrupt the bacterial heat-shock protein repair system. Importantly, this insect peptide does not bind to the human equivalent of the DnaK receptor, known as Hsp70, greatly enhancing its pharmaceutical potential in humans. If the peptide bound to the human Hsp70 receptor, it and related compounds might pose a danger to human cells.
With the receptor now identified, scientists might be able to develop new drug compounds with improved characteristics that act on the same site. The new compounds might be more easily synthesized than the naturally occurring one, for example, or show greater stability in mammalian systems. They might also be tailored to target specific bacterial or fungal strains with heightened effectiveness.
Other Wistar co-authors on the study are postdoctoral trainee Insug O; research technicians Patricia J. Consolvo and Barry A. Condie, and assistant professor Magdalena Blaszczyk-Thurin, Ph.D. Additional co-authors at other institutions are Mark E. Rogers, M-Scan Inc.; Sandor Lovas, Creighton University; and Philippe Bulet, Institute de Biologie Moleculaire et Cellulaire. Funding for the research was provided by the National Institutes of Health.
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