The antibiotic binds so tightly to the peptidoglycan that the bacteria can no longer use the machinery to make their cell wall and thus die.
Unfortunately, bacteria have found a way to alter the peptidoglycan in such a way that the antibiotic can no longer grab hold. Think of it as trying to hold a ball without any fingers. Biochemically the bacteria express a mutant form of the peptidoglycan in which properties of a key atom used in the recognition process are changed. This simply means where there once was something attractive there is now something repulsive. Chemically, the bacteria replace an amide (carbonyl, RC=O linked to an amine) with an ester (a carbonyl, RC=O linked to an oxygen, O).
This one atom change changes the entire game and renders vancomycin ineffective. Until now.
Like magnets, molecular interactions can be attractive (oppositely charged) or repulsive (identically charged). What chemists in the Boger lab have done is made this key interaction no longer repulsive, but attractive.
So now the new vancomycin analogue can grab hold of the mutant peptidoglycan, and again prevent the bacteria from making the cell wall and killing the resistant bacteria. But what is so remarkable about the design is that the redesigned antibiotic maintains its ability to bind the wild type peptidoglycan as well.
Changing the properties of a key amide at the core of the natural products structure required a new synthetic strategy that only the most talented chemists could achieve in the lab. The preparation of the entire structure took a great deal of time and a fresh approach.
The new compound has an amidine (an iminium, RC=NH+ link
|Contact: Mika Ono|
Scripps Research Institute