One of the most powerful methods for new drug discovery is the use of protein X-ray crystallography. Many pharmaceuticals exert their biological action by binding to enzymes present in the body. If that enzyme can be isolated and if it can be convinced to solidify into a specific crystalline form known as a “single crystal”, then scientists can analyze the structure of the protein by bouncing X-rays through the crystal. The end result of this analysis is a 3-dimensional computer graphic image of the molecule, showing clearly how the atoms are connected and showing the positions of all of the atoms in relationship to each other.
This is a powerful tool for chemists as it is this three-dimensional shape which controls what molecules are able to interact with the enzyme. Enzyme follows a “lock and key” model of reactivity. If an incoming molecule, the “key”, has the precise molecular shape to interact with the enzyme (the “lock”), then the key will slide into position in the lock and undergo a chemical reaction. Molecules which do not have this precise shape will not be able to undergo reaction. Just like any locksmith, if chemists have a detailed image of the interior of the enzyme, they can design a key (reactant molecule) which has the necessary shape to react. If chemists isolate an enzyme from bacteria and identify weak spots – chinks in the bacterias defense – then they can design an antibiotic molecule which will lock into the enzyme and destroy it. Bacteria, like all cells, rely on their enzymes to accomplish all of their chemical reactions and so if the bacterial enzymes are destroyed, the bacterium dies.
Once the molecule has been designed on paper – or in the computer, as is a more accurate description of the process – this sketch can be given to synthetic organic chemists, who design a synthesis of the molecule starting with whatever common chemicals they have available to them from chemical supply houses. The result is a unique antibiotic which has a high affinity for the bacterial enzymes.
A common chemical structure found in antibiotics is a structure called a beta-lactam ring. Penicillin is a classic example of a beta-lactam drug. Many bacteria have begun to build up a resistance to this structure, however. Scientists have performed X-ray crystal analysis of enzymes from antibiotic-resistant bacteria and discovered that it was this lactam ring common feature that the bacteria had evolved to resist. The ring is four-sided, in the shape of a square; the weak link in the bacterial enzymes had modified their molecular structure so that this shape no longer acted as a key. Without this strong interaction, the molecules lost their antibiotic activity.
Scientists from Europe now describe in the journal Nature: Chemistry how, by using X-ray crystallography, they have deciphered the binding sites from these modified enzymes and have concluded that a pair of pentagonal, five-membered rings (instead of the single square ring) is now the correct shape to precisely match the enzymes requirements. Using that knowledge they were able to design a new antibiotic, phenoxyacetyl-LTV, which is extraordinarily successful at killing bacteria. Bacteria that have become resistant to typical beta-lactam antibiotics have absolutely no resistance to the LTV antibiotic, and are rapidly killed.
The battle between synthetic chemists and bacteria will continue to rage. Bacteria reproduce rapidly, and they adapt quickly. However, as long as scientists continually monitor the changes in the bacterial enzymes and continually produce updated versions of antibiotics, we should be able to stay ahead of the game.
The source of this article can be found at: http://www.nature.com/nchembio/press_releases/nchembio0907.html