Center for Drug Discovery screening center uncovers strategy to fight superbug crisis

Two male scientists in a laboratory working at a fume hood with complex chemical equipment, glass panels covered in handwritten molecular structures, and one holding a syringe. — Researchers Webster Santos, left and Zhaomin Yang utilize the Center for Drug Discovery’s screening center to screen a library of compounds. Photo by Felicia Spencer for Virginia Tech.

According to the Global Burden of Disease Antimicrobial Resistance Collaborators, an estimated 169 million cumulative deaths over the next 25 years will be associated with and attributable to antimicrobial resistance.

This escalating public health crisis is fueled by the widespread use, overuse, and misuse of antibiotics in both clinical and agricultural settings, making bacterial infections increasingly difficult to treat

Now, researchers at Virginia Tech are changing the rules of engagement.

Instead of trying to kill the bacteria, Zhaomin Yang and Webster Santos, researchers at the Virginia Tech Center for Drug Discovery, are investigating how to reduce pathogenicity (the ability of a microbe, such as a bacterium, virus, fungus, or parasite to cause disease in a host such as a person, dog, or plant, by removing its armor– the bacterial pili).

Pili are hair-like bacterial appendages that act like a combination of armor and grappling hooks, which are used to adhere to host cells, other bacteria, and surfaces. Much like the legs with sticky feet of a gecko, bacteria use type IV pilus (T4P) to attach to human cells, stick to surfaces, and link up with other bacteria to cause infections. Once attached, the pili retract, pulling the bacteria close to host cells to establish an infection.

The Center for Drug Discovery’s screening center afforded the researchers the opportunity to screen a library of compounds and discover several molecules including benserazide that inhibited bacterial infection. With early backing from the Virginia Tech Center for Emerging, Zoonotic, and Arthropod-borne Pathogens (CeZAP) and the Commonwealth Health Research Board (CHRB), the team initiated a structure-activity relationship profiling on the molecule and discovered better analogs.

Through this success, the duo has been awarded a National Institute of Health R21 Multiple Principal Investigator (MPI) grant, which funds high-risk, high-reward exploratory research.

The team will continue to improve benserazide analogs and screen thousands more compounds for entirely new classes of T4P-targeting drugs to develop inhibitors against the bacterial type 4 pilus as a virulence factor. Such antivirulence agents allow bacteria to survive but block their ability to infect humans. If successful, these drugs have the potential as the next generation of designer chemotherapeutics to overcome antibiotic resistance.

The power of this new screening method has already yielded incredible real-world proof-of-principle results. Utilizing the high-throughput screening center housed within the Fralin Life Sciences Institute, the team identified benserazide—an FDA-approved drug traditionally used for treating Parkinson’s disease—as a potent inhibitor of T4P function.