Scientists Uncover Vulnerable Enzyme that Can be Targeted to Kill Dangerous Pathogens

BALTIMORE – A collaborative study conducted by researchers from three institutions in the U.S. has shown that an enzyme, which is essential to many bacteria, can be targeted to kill dangerous pathogens.

Experts at Burnham Institute for Medical Research (Burnham), University of Texas Southwestern Medical Center and University of Maryland have also identified chemical compounds that can inhibit this enzyme, and suppress the growth of pathogenic bacteria.

Writing about their study in the journal Chemistry and Biology, the researchers say that their findings are essential to develop new broad-spectrum antibacterial agents to overcome multi-drug resistance.

Dr. Andrei Osterman, an associate professor in Burnham’s ioinformatics and Systems Biology program, targeted the acterial nicotinate mononucleotide adenylyltransferase (NadD), an essential enzyme for nicotinamide adenine dinculeotide (NAD) biosynthesis, which has many crucial functions in nearly all important pathogens.

The bacterial NadD differs significantly from the human enzyme.

“It’s 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,” said Dr. Osterman.

The research team used a structure-based approach to search for low-molecular-weight compounds that would selectively inhibit bacterial NadD, but not the human equivalent, by screening, in silico, more than a million compounds.

In their experiments, they tested the best predicted compounds against Escherichia coli and Bacillus anthracis (anthrax), which led them to a handful of versatile inhibitory chemotypes, which they explored in detail.

Using protein crystallography, a 3D structure of the enzyme in complex with one of the inhibitors was solved providing guidelines for further drug improvement.

“This is proof-of-concept that NadD is a good target to create antibacterial agents. 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,” said Dr Osterman.

The research was supported by a grant from the National Institute of Allergy and Infectious Diseases.