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Poking Holes In Pathogens: Scientists At The Scripps Research Institute Build A New Class Of Nanotube "Smart Drugs"

Date:
July 26, 2001
Source:
Scripps Research Institute
Summary:
Scientists at The Skaggs Institute for Chemical Biology, a part of The Scripps Research Institute (TSRI), have published a paper in the current issue of Nature that describes a broad nanochemical approach for designing drugs to combat such problems as infections with antibiotic resistant bacteria.
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La Jolla, CA, July 25, 2001 -- Scientists at The Skaggs Institute for Chemical Biology, a part of The Scripps Research Institute (TSRI), have published a paper in the current issue of Nature that describes a broad nanochemical approach for designing drugs to combat such problems as infections with antibiotic resistant bacteria.

Principal Investigator M. Reza Ghadiri, Ph.D., Professor of Chemistry at TSRI, and his coworkers have created a class of biological polymers known as cyclic peptide nanotubes, which stack inside the cell membranes of bacteria, and poke holes in their membranes, killing the cells.

These "nanotube" stacks have demonstrated strong bactericidal activity both in the test tube and in living tissue against a number of deadly pathogens including mutlidrug-resistant Staphylococcus aureus, one of the most common hospital-acquired infections. Antibiotic- resistant bacteria are a growing public health threat worldwide, and the World Health Organization estimates the total cost of treating all hospital-borne antibiotic-resistant bacterial infections is around $10 billion a year.

Ghadiri describes his nanotubes as small, smart assemblies that have the ability to sense and respond to their environment. He hopes that since these are synthetic molecules, bacteria will be slower to develop resistance to them. "The bacteria haven't seen these before," he says.

The research article, "Antibacterial Agents Based on the Cyclic D, LPeptide Architecture," appears in the July 26, 2001 issue of the British science journal Nature and is authored by Sara Fernandez-Lopez, Hui-Sun Kim, Ellen C. Choi, Mercedes Delgado, Juan R. Granja, Alisher Khasanov, Karin Kraehenbuehl, Georgina Long, Dana A. Weinberger, Keith Wilcoxen, and M. Reza Ghadiri.

All the protein molecules found in cells are composed of amino acid subunits that are chiral molecules, one of two non-superimposable mirror image forms, like your right and left hand.

In nature, only the L-a-form of amino acids (left-handed) are used to make peptides, or proteins, but there are no such constraints in the laboratory.

Ghadiri and his colleagues built peptides by putting alternating right and left-handed amino acids together into short 6 and 8 amino acid chains, and then joining the two ends of the chain together. Because of their unusual alternating right and left handedness, these "cyclic" peptides are flat and round, like a donut.

By altering the amino acids from which the cyclic peptides were built, Ghadiri and his colleagues were able to design them to insert themselves into bacterial cell walls in a highly specific way. Inside the walls of a bacterium, these cyclic peptides spontaneously self-assemble into nanotubes, like donuts on a string.

These nanotubes effectively poke holes in the cell walls and disrupt the normal electric potential and ion gradients that bacteria use to maintain homeostasis, generate energy, and carry out important chemical reactions necessary for survival. By forming nanotubes and poking holes in the cells, cyclic peptides disrupt the gradients and kill the cells.

Moreover, says Ghadiri, the cyclic peptides represent a broader approach to drug design because the antibiotic properties of the compound come when the cyclic peptides self-assemble into the nanotubes. By making changes to the types of amino acids that make up these cyclic peptides, nanotubes can be specifically targeted to disease-causing bacteria without effecting healthy host tissues.

Also, these sorts of compounds may minimize the chance of bacteria developing resistance, because the compounds are fast acting and bacteria would have to make wholesale changes to their membrane composition to develop resistance.

The research was funded in part by National Institutes of Health and The Skaggs Institute for Research.


Story Source:

The above story is based on materials provided by Scripps Research Institute. Note: Materials may be edited for content and length.


Cite This Page:

Scripps Research Institute. "Poking Holes In Pathogens: Scientists At The Scripps Research Institute Build A New Class Of Nanotube "Smart Drugs"." ScienceDaily. ScienceDaily, 26 July 2001. <www.sciencedaily.com/releases/2001/07/010726101824.htm>.
Scripps Research Institute. (2001, July 26). Poking Holes In Pathogens: Scientists At The Scripps Research Institute Build A New Class Of Nanotube "Smart Drugs". ScienceDaily. Retrieved May 23, 2015 from www.sciencedaily.com/releases/2001/07/010726101824.htm
Scripps Research Institute. "Poking Holes In Pathogens: Scientists At The Scripps Research Institute Build A New Class Of Nanotube "Smart Drugs"." ScienceDaily. www.sciencedaily.com/releases/2001/07/010726101824.htm (accessed May 23, 2015).

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