New Antibiotics Outsmart Evolving Bacteria

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

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




UBC Spins Off New Companies

The UBC University-Industry Liaison Office has overseen
the creation of three new spinoff companies so far this

In addition to Indel, Vida Therapeutics has been established
around the work of Dr. David Granville to focus on the discovery
and development of first-in-class drugs for the treatment
of age-related degenerative processes, cardiovascular disease
and other inflammatory conditions.

Boreal Genomics, based on the discoveries of Drs. Andre Marziali
and Lorne Whitehead, has a novel mechanism that purifies
DNA so that it is possible to analyze samples that would
previously have been deemed contaminated. This technology
has a wide range of potential applications as a medical device,
and as a research tool in areas such as forensics and archaeology.