Scientists Uncover Vulnerable Enzyme that Can be Targeted to Kill Dangerous Pathogens
Experts at Burnham Institute for Medical Research (
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.
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
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
The research was supported by a grant from the National Institute of Allergy and Infectious Diseases.