In the battle against antibiotic resistant bacteria, McMaster University researchers have found resistance itself is a successful pathway for discovering new antibiotic drugs.

"In essence, we’ve made resistance useful instead of a scary problem," said Gerry Wright, professor and scientific director of the Michael G. DeGroote Institute for Infectious Disease Research.

Last month, the Centres for Disease Control and Prevention in the United States warned that the overuse of antibiotics in medicine and agriculture has fostered germs that are resistant to every known antibiotic, causing infections for which there are no treatment. Coupled with this, there has been a drastic decline in the number of new antibiotics developed in the last 25 years.

Wright said one of the challenges in discovering new antibiotics is finding the source of new chemicals that may have antibiotic properties.

Most of today's antibiotics were discovered between 1940 and 1960, when bacteria and fungi that grow in the environment were screened. Penicillin and many anticancer drugs were discovered this way.

"It turns out that bacteria that live in the soil are great producers of antibiotics and other medicine," said Wright, adding many agree that soil bacteria and fungi are still the best source of new drug candidates. However, the challenge of collecting and testing millions of strains to find new lead compounds for potential new antibiotics is like trying to find a needle in a haystack, he explained.

Gerry Wright (far left) poses with members of his lab involved in the study. From left: Nick Waglechner, Peter Spanogiannopoulos, Ricardo Medina, Andrew King, Wenliang Wang and Maulik Thaker. Photo credit: Chantall VanRaay

Researchers in Wright's lab wondered if there was another way to run screens (a drug discovery process) to tackle this problem.

"We questioned what would happen if we applied resistance as a filter to find new drug candidates," said Maulik Thaker, a postdoctoral researcher who led a study on this process which was published in the current issue of Nature Biotechnology. "We were surprised when we noticed a dramatic increase in the ‘hit rate’ by reducing the size of the haystack."

The new procedure let researchers screen for new drugs 10,000 times more effectively than in the past. Researchers discovered:

• A new antibiotic called pekiskomycin from a new soil bacteria obtained from Pekisko, Alberta
• New producers of antibiotics called rifamycins
• New therapeutics, such as an anti-cancer compound called qeldanamycin

The team also designed tests that let researchers distinguish between different types of antibiotic subgroups. Using snippets of DNA that code for known classes of drugs and sophisticated new software programs, they construct patterns that identify strains of soil bacteria that may be producing new antibiotic and anticancer compounds.

The implications are significant, said Thaker, because pharmaceutical companies are reluctant to invest in new antibiotics due to the significant cost of drug development and a drug's short lifespan caused by antibiotic resistance.

"But we can offer a way to zero in on a handful of drug producing strains of soil bacteria instead of sifting through tens of thousands, or millions. Then, it becomes a viable business model for finding new molecules more rapidly," he said.

The research was carried out at McMaster’s Centre for Microbial Chemical Biology and the Michael G. DeGroote Institute for Infectious Disease Research, and was supported by grants from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council and Wright’s Canada Research Chair in Molecular Studies of Antibiotics.

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