There is more than one way to kill a bacterium.
Antibiotics are small molecules that kill bacteria by preventing them from growing or reproducing. Antibacterials such as antiseptics are fully synthetic bacterial killers. Antibodies are highly specific proteins that target bacteria for destruction by the body.
Each of these treatments has its limits. Bacteria can build resistance to antibiotics. Antiseptics are toxic if taken internally. And antibodies can be fragile, unable to withstand the acids and enzymes of the digestive tract when taken orally.
Since patients generally prefer medications taken orally rather than by IV or injection, there is a huge need for something new. IPI is attempting to make a novel generation of medicines, created from smaller, more durable proteins than antibodies.
IPI’s Protein Design Laboratory is generating a repertoire of mini-proteins, small stretches of amino acids that can perform very specific functions, like binding to a specific bacterium, by virtue of their intricate structures. The Lab’s mini-proteins are replete with stabilizing bonds between sulfide groups. These provide durability, which translates to a longer shelf-life and eliminates the need for refrigeration. This ease of storage when compared to biologics is a game changer. And mini-proteins could be taken as a pill.
The inspiration for these mini-proteins came from molecules produced in nature — like those produced in snake venom, and by insects and mollusks for defense. But unlike the naturally occurring mini-proteins, the Lab, headed by Chris Bahl, is designing mini-proteins via a computer.
“We have devised an innovative strategy that builds upon our recent advances in computational de novo protein design,” Bahl says.
IPI’s mini-proteins are fully synthetic and varied. Each of the million novel mini-proteins in IPI’s library is designed intentionally to be as different from the others as possible, and the variety needs to be perfect. This curated diversity takes into account many factors, including charge, hydrophobicity and shape. The resulting designs will be synthesized as DNA, expressed in yeast and screened via IPI’s unique platform.
Because nothing like this has been done, the project is high-risk, high-reward. To hedge their bets, the Bahl lab is beginning with a “proof-of-concept” effort that involves the engineering of robust mini-proteins that specifically bind to two exotoxins produced by Clostridium difficile, the single most common cause of healthcare-associated infections in the US. These durable anti-virulents are yet another class of treatments: fighting against the product of the invader instead of the invader itself.
The IPI team will isolate and sequence the best binders, scaling up for further testing.
“These technologies could move the needle of global public health,” Bahl says. “We could treat diseases outside of a traditional health-care setting and take these drugs honestly … anywhere.”