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Undergraduate members in Samantha Grenheid’s microbiology laboratory course studying strains of naturally-occurring resistant microbes. (McGill Reporter)

McGill labs find new ways to target resistant bacteria

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In 1945, Alexander Fleming, made famous for his discovery of penicillin, warned that excessive antibiotic use would likely result in bacteria developing resistance. The term is often in the headlines, but what exactly is antibiotic resistance? It is generally defined as microorganisms developing the ability to somehow prevent the intended effects of the antibiotic. That somehow is a key area of research that spans almost all STEM disciplines.

McGill Biochemistry Professor Albert Berghuis and his lab are working to find interdisciplinary solutions against antibiotic resistance. 

“We are really at the interface of physics and biology, we want to know what is actually happening in a superbug in extreme detail,” Berghuis said.

Indeed, in a recent paper published in Structure, Berghuis’ lab demonstrated their attention to such detail.

The rigorous study proposes the mechanism and shape—or conformation—of a protein which causes resistance. Usually, bacteria respond to an antibiotic threat—that is, the presence of antibiotics in their surroundings—by producing proteins to inactivate the drugs. As those proteins are only needed when the bacteria are under threat, their production depends upon the presence of that threat.

“I grew up in the Cold War, and I remember that the US spent a lot to maintain [….] defence and early warning systems,” Berghuis said. “In the same way, bacteria must expend a lot of energy and resources to maintain defence systems against antibiotics.” 

However, the protein studied by Berghuis’ lab works rather differently: it acts as a sort of ‘molecular mousetrap,’ storing energy for use when it is required.

When present, antibiotics bind to the protein and change its shape causing the mousetrap to ‘spring.’ As a result of the protein’s conformation change, chemical groups are positioned closer to the antibiotic, allowing the protein to deactivate the antibiotic. This mechanism provides newfound insight into how bacteria develop resistance, opening a new pathway for drug development that would muzzle the mechanism’s ability to resist antibiotic treatments.

Despite the recent breakthrough, the overall outlook with regard to antibiotic resistance is bleak. Reports from the World Health Organization (WHO), Centers for Disease Control (CDC), and articles in various media outlets—most recently The Economist—have suggested that we have entered a post-antibiotic era, in which antibiotics have been rendered ineffective.

Nevertheless, Associate Microbiology Professor Samantha Gruenheid noted that these reports could actually be a positive sign. 

“Awareness of antibiotic resistance has increased in the past few years [….] and there are some excellent scientists working on the problem,” Gruenheid said. “Work like that of Professor Berghuis here at McGill opens up new ways to interfere with antibiotic resistance.”

Last year, as Dr. Gruenheid pointed out, an international team conducted experiments on soil microbes that led to the discovery of “a whole new class antibiotic–the first in 30 years.”

The McGill chapter of Small World Initiative provides hands-on antibiotic resistance research for microbiology undergraduates. (Small World Initative)
The McGill chapter of Small World Initiative provides hands-on antibiotic resistance research for microbiology undergraduates. (Small World Initative)

In addition, Dr. Gruenheid launched a McGill chapter of a program started at Yale University known as the Small World Initiative (SWI). The program seeks to provide students with an opportunity for real, hands-on microbiological research while also working to fight against antimicrobial resistance.

“The SWI is aiming to actually find new candidates to replenish the antibiotic pipeline,” Dr. Gruenheid said. “Over two-thirds of antibiotics originate from soil microbes, and by having all the SWI students searching for novel antibiotic producing microbes within the soil in their own environments, the SWI is combining the power of crowdsourcing with the approach of looking in a wide variety of geographic locations for antibiotic producers.”

 “SWI is currently in United States, Belize, Canada, Iraq, Ireland, Jordan, Malaysia, Nigeria, the Philippines, and the United Kingdom,” Dr. Gruenheid added, “which increases the chances of discovering something novel.” 

Microbiology graduate student Tyler Cannon, now in Dr. Grueinheid’s lab, helped co-ordinate the effort to set up the SWI at McGill as an undergraduate. He was subsequently recognised by the Canadian Society of Microbiologists for his work, and is currently following up on promising strains found by U1 students in the Microbiology and Immunology program at McGill.

“I was really shocked when we started getting positive hits,” Cannon said. “In fact, about 15 per cent of all the isolated [bacterial strains] I tested were positive for antibiotics—a number I couldn’t believe.”

Cannon and Dr. Gruenheid’s lab have since reached out to various academics and professionals to further investigate those promising strains found at McGill.

“This summer [….] we started collaborating with a new [Principal Investigator] in Laval who’s willing to do full genome sequencing for us, but we’re still waiting for results,” Cannon said. “[And] although it’s still preliminary, [.…] there were actually two samples that showed promise for being novel.”

Although the issue of antimicrobial resistance is finally receiving attention and new solutions are being investigated, it may be too little too late. None of the professors interviewed were willing to say that they were optimistic about the future of research in the field.

“I could be both optimistic or pessimistic [….] I don’t know which to start with,” said Professor Berghuis.

Dr. Gruenheid agreed that while advancements have been made, the overall outlook on antibiotic resistance is bleak.

“On a good day, I like to think I am cautiously optimistic,” Dr. Gruenheid said. “On the other hand, bacteria now exist that are resistant to every antibiotic, including the so-called ‘drugs of last resort.’”

This statement rings truer now than ever before: A recently-published paper in the European Respiratory Society details the treatment of a patient with XDR-TB—extensively-drug-resistant tuberculosis—which took 38 months to treat as well as an individualized treatment plan involving more than six antibiotics. The case was notable as two ‘last resort’ antibiotics had to be used in conjunction for the first time ever.

The lack of new antibiotics was a common concern for both professors. 

“The pharmaceutical industry is waiting more and more on academia to do the basic research and then picking it up,” Berghuis said. 

“The current pipeline for antibiotic development is almost dry. Drug development all the way to the clinic is long and very expensive,” said Dr. Gruenheid.

With basic research funding low and little appeal for pharmaceutical companies to develop drugs which are taken in short bursts, as opposed to drugs for chronic diseases, there are few resources left to combat antibiotic resistance. Amid all the reports by public health agencies, physicians, researchers, and politicians, the future of antimicrobial research is still uncertain.

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