Bacterial Enzyme May Become Target for a New Generation of Antibiotics

Microbiologists have identified an enzyme critical to the survival of many types of pathogenic bacteria that may be the target for a new generation of antibiotics.

Investigators from the Burnham Institute for Medical Research (La Jolla, CA, USA) isolated the enzyme nicotinate mononucleotide adenylyltransferase (NadD) from both Escherichia coli and Bacillus anthracis, where it was critically involved in nicotinamide adenine dinculeotide (NAD) biosynthesis.

The investigators employed a computerized screening technique to evaluate more than one million chemical compounds for the ability to inhibit bacterial NadD without having an effect on the human version of the enzyme. They reported in the August 28, 2009, online edition of the journal Chemistry & Biology that a small number of the compounds effectively inhibited NadD from E. coli and B. anthracis. A three-dimensional structure of the enzyme complexed to one of the inhibitors was obtained, providing mechanistic insights and guidelines for further improvement.

"This is proof-of-concept that NadD is a good target to create antibacterial agents,” said senior author Dr. Andrei Osterman, associate professor of bioinformatics and systems biology at the Burnham Institute for Medical Research. "This knowledge will be useful for both biodefense and public health. The next step is to find better inhibitors. We do not have a silver bullet yet, but we are certainly hitting a golden target. It is clear that because of bacterial resistance, we need new, wide-spectrum antibiotics. This enzyme is indispensable in many pathogens, so finding ways to inhibit it could give us new options against infection.”

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Burnham Institute for Medical Research