Battle against bacteria

Enzyme targeted as key to development of new antibiotics

By: John Gregg

Posted: 11/9/09

Andrei Osterman, Ph.D. of the Burnham Institute for Medical Research and colleagues recently have shown a way to slow the growth of infectious antibiotic-resistant bacteria like Staphylococcus (Staph) , which could in turn produce superior antibiotics in the future.

Using available technology to map dozens of microbial genomes, researchers were able to identify specific vulnerabilities in several pathogens. These vulnerabilities are essential enzymes that bacteria must have in order to grow. Scientists hope to one day develop new drugs that would prevent the normal production of these enzymes.

"Our most optimistic expectation is that our work, which at this point is just a proof of concept, will ultimately lead to the development of a new broad spectrum antibiotic, which will take its due place in ranks of our anti-infective agents," Osterman told the Voice.

The studies at Burnham focused on a particular enzyme called nicotinate mononucleotide adenylyltransferase (NadD), which is necessary for production of the coenzyme nicotinamide adenine dinucleotide (NAD).

NAD is found in all living cells, although, the human form differs from that found in bacteria. NAD is needed for bacteria metabolism and, therefore, growth, propagation and survival. By preventing the production of NadD, the supply of NAD is cut off, and bacteria are unable to grow at a normal rate.

"The need for new targets was dictated by the emerging microbial resistance to nearly all existing classes of antibiotics that were historically developed against a very limited set of targets," said Osterman. "Therefore, inhibitors of NadD enzyme, if they could be developed, would become prototypes of novel antibiotics."

The study's follow-up research was partially conducted at the University of Texas Southwestern Medical Center. Using a method called protein crystallography, Osterman's colleagues were able to create a 3-D view of the NadD bacterial enzyme. This will help with future study and is a key point in the process of developing new medicine.

Antibiotic-resistant strains, such as Methicillin-resistant Staphylococcus aureus (MRSA), cause thousands of deaths per year. Scientists are attempting to modify existing drugs to increase their effectiveness. Some are even attempting to make bacteria more vulnerable to current drugs.

However, as Osterman noted, existing antibacterial agents become less powerful with time. Creating new medication is expected to combat drug resistance on a broader scale.

With the creation of "super antibiotics" comes the risk of creating more "super bugs." The findings at Burnham suggest resistance could become less of a concern if such essential enzymes are destroyed.

"Bacteria are indeed very versatile in developing and propagating resistance," said Osterman. "There are several reasons to think that our strategy may be somewhat more robust than traditional antibiotics."

Osterman went on to say his colleagues selected NadD because bacteria cannot simply abandon this enzyme in order to become resistant. This means pathogens would be left extremely vulnerable to drugs specifically attacking the gene. Mutations are also less likely to occur because of the nature of NadD.

Unfortunately, bacteria will develop resistance to any agent given enough time. For this reason, the hope is to eventually develop several new antibiotics at the same time.

The strategy in this case would be to hit a resistant pathogen with a second drug, or third if necessary, in order to maintain widespread control of infections. Osterman noted, however, it could take more than 10 years before such antibiotics are marketed to patients.

"No matter how disappointing it sounds, the earlier we start the earlier we get there," said Osterman. "There is no way around, and the bottlenecks, time and money, are not in research but in clinical and regulatory issues."

There are also other possible ways to battle super bacteria. Osterman acknowledged the future possibility of building up natural immunity to certain pathogens. One option is to continue development of existing vaccines.