Nanobiotics

Conventional anti-biotics such as penicillins etc function metabolically, by interfering with bacterial synthesis of the cell wall. Many bacteria have evolved to develop resistance to common anti-biotics, and some bacterial are resistent to most. In 1993, a new approach to developing such agents was pioneered. Reza Ghadiri at the Scripps Research Institute in California developed a series of cyclic peptides using a combination of the natural (l) form with the un-natural (d) amino acid enantiomer. It has been known for some time that the stacking of crystals composed entirely of molecules of one chiral form (all in a so called R or an S configuration) can be quite different from the racemic form of the same molecule, which contains equal amounts of R and S isomers. For example, the racemic form (R,S) of the Pirkle reagent forms an infinite chain of hydrogen bonded interactions in the solid state (left structure), whereas the enantiomerically pure S form forms self-recognising dimers of a quite different type (right structure). [To view the structures, install Chime in your browser: http://www.mdli.com/ ]
Exactly the same happens with the the cyclic peptides synthesised by Ghadiri's group. This time, the R and S forms are created by coupling different amino acids, and not simply taking a racemic mixture of each. The monomeric structures of these peptides are shown below. Notice particularly how water of crystallisation occupies the central cavity, and how water-hating (lipophilic) groups occupy the outside rim

In the solid state, just like the (R,S) Pirkle reagent, these cyclic peptides form an infinite chain, this time with the rings interacting via hydrogen bonds by stacking on top of each other. This results in alignment of the central cavities to form a tube or channel, filled with water molecules. Adjacent tubes interact via dispersion forces aligning the lipophilic rims. The result is a membrane-like "nanostructure". If you rotate the structure below, you will eventually see five channels occupied by the (red) water molecules, but you have to get the orientation exactly orthogonal to see the effect.
When added to a culture of penicillin-resistant bacteria, these nanobiotics are thought to insert into the lipophilic cell membrane. Here, surrounding solvating water is removed, and the peptide rings instead stack into the ziggurat, in a manner analogous to the crystal structures shown above. The resulting channels allow water and other hydophilic species (e.g. glucose) to drain out of the cell, killing it in around 15-20 seconds. By altering the precise nature of the amino acids comprising the cyclic peptide, various specific nanobiotics can be engineered. Unlike conventional anti-biotics therefore, these substances do not function chemically but in essence mechanically, at a true nanomolecular scale.

For further reading, see

  1. New Scientist Feature by Trisha Gura
  2. "Peptide Nanotubes and Beyond", Jeffrey D. Hartgerink, Thomas D. Clark, M. Reza Ghadiri, Chemistry, 1998, 4,1367-1372.
  3. J. Sanchez-Quesada, M. R. Ghadiri, H. Bayley, and O. Braha, J. Am. Chem. Soc., 2000, 122, in press.
  4. H. Rapaport, H. Sun Kim, K. Kjaer, P. B. Howes, S. Cohen, J. Als-Nielsen, M. R. Ghadiri, L. Leiserowitz and M. Lahav, J. Am. Chem. Soc, 1999, 121, 1186.
  5. T.D.Clark, J.M.Buriak, K.Kobayashi, M.P.Isler, D.E.McRee and M.R.Ghadiri, J.Am.Chem.Soc., 1998, 120, 8949.
  6. M.R.Ghadiri, K.Kobayashi, J.R.Granja, R.K.Chadhaand D.E.McRee, Angew.Chem.,Int.Ed.Engl.,1995, 34, 93.
  7. "Photoswitchable Hydrogen-Bonding in Self-Organized Cylindrical Peptide Systems", M. S. Vollmer, T. D. Clark, C. Steinem, M. R. Ghadiri Angew. Chemie Int. Ed. 1999, 38, 1598-1601
  8. For details of the Pirkle reagent, H.S. Rzepa, M. L. Webb, A. M. Z. Slawin and D. J. Williams, J. Chem. Soc., Chem. Commun., 1991, 765.
  9. Another cyclic peptide related to the ones described here is Gramicidin S. View its structure here.