Targeting virulence to disarm the pathogen: Enzyme-activated-substrate inhibition of Anthrax edema factor.

Since the discovery by Fleming that a mold could inhibit the growth of bacteria, each new antibiotic developed to treat infections quickly lost its efficacy due to the emergence of resistant strains. As a result, the ongoing threat by antibiotic-resistant pathogens would benefit from new strategies to combat bacterial infections. An ideal drug is one which is efficacious, can limit selective pressure against the pathogen, and potentially augment the currently available antibiotics to restore their efficacy. Targeting virulence factors used by bacteria to establish infections has the potential to meet these goals. Anthrax edema factor (EF), an adenylate cyclase secreted by Bacillus anthracis, which causes anthrax, is an example of this type of virulence factor. Our previous work showed that the activity of EF can be blocked with small molecule covalent inhibitors targeting the catalytic site. The current report extends this work with the discovery of enzyme-activated-substrate inhibitors which display improved drug-like properties and stability.