Indel Therapeutics CEO Malcolm Kendall and Dr. Neil Reiner have a big idea for a new class of antimicrobial drugs - photo by Don Erhardt

UBC Reports | Vol. 54 | No. 11 | Nov. 6, 2008

New Antibiotics Outsmart Evolving Bacteria

By Catherine Loiacono

It started with the discovery of a hairpin loop in an essential protein found in both humans and parasites.

Now a research team at the University of British Columbia, in collaboration with a recently launched UBC spinoff company, Indel Therapeutics Inc., is developing new classes of antimicrobial drugs for difficult-to-treat and hospital-acquired infections. The spinoff is one of three overseen this year by UBC’s University-Industry Liaison Office.

Historically, antimicrobial drug development, which includes antibiotics, antifungal, and antiviral therapies, targeted the proteins in pathogens that are not found in humans, allowing humans to combat these disease-causing bugs.

Indel Therapeutics’ approach, on the other hand, targets essential proteins that are found in pathogens and in humans. These proteins perform critical housekeeping chores that keep cells in all species alive and functioning.

“The high percentage of similarities between essential proteins in humans and pathogens has historically left this type of research off-limits,” says Dr. Neil Reiner, professor and head of UBC’s Division of Infectious Diseases in the Faculty of Medicine. “We discovered that while these proteins are found in both the pathogen and humans, there are subtle differences called insertions or deletions or “indels” that allow targeting the bug version of the protein, without affecting the human counterpart protein,” says Reiner. “For example, a critical protein in the pathogen that causes Leishmaniasis (a disease prevalent in the developing world) is missing a hairpin loop sequence that is present in the same essential human protein, creating a pocket we can target with a small molecule drug.”

The new classes of antimicrobials that Indel Therapeutics is developing will selectively bind in the deleted region but cannot bind in the corresponding human protein. In doing so, the pathogen dies because the essential protein is blocked. Targeting essential proteins in this way is a new mechanism for attacking these disease-causing bugs.

“One of the significant benefits of this new class of antimicrobials is it will be difficult for microbial resistance to evolve,” says Reiner. “The explosion in antibiotic-resistant bacteria continues to drain our medical chest of antibiotics. These pathogens can undergo as many as 500, 000 generations for every one of ours. This gives them a great evolutionary advantage to mutate and become resistant to antibiotics. As a result, a third of all deaths are because of infection.”

Indel Therapeutics’ antimicrobials drugs will target a wide range of important pathogens including; methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus, E.coli, Salmonella, Malaria, Leishmaniasis, African Sleeping Sickness and others.

The company anticipates that it will take three years before the discovery is introduced into human clinical trials.

“The rapid evolution of drug-resistant pathogens will continue to drive the need for new antibiotics with novel mechanism of action,” says Malcolm Kendall, CEO, Indel Therapeutics. “Our approach is unique in that it targets -- with great specificity -- critically essential protein within pathogens, and this targeting strategy should confer an advantage against the emergence of resistance.”

According to Kendall, the number of new antibiotics approved by the Food and Drug Administration (F.D.A.) has declined 75 per cent over the last 24 years with only 4 antibiotics being approved in the last few years and only three novel classes of antibiotics being introduced in more than 40 years. The cost of hospital-acquired infections is as much as $27.5 billion in additional hospital costs to the U.S. healthcare system.