Megan Tu and Eric Brown have discovered new vulnerabilities in some of the world’s most drug-resistant bacteria. Credit: McMaster University
Normally, scientists study bacteria in the richest conditions possible in the laboratory. It’s how research has functioned for over 100 years, and it works.
However, in Eric Brown’s laboratory at McMaster University, scientists do the exact opposite: study bacteria under nutrient stress. Brown, a biochemistry and biomedical sciences professor at the Canadian University, says his lab has had a longstanding interested in doing it this way—and recently, it paid off.
In a new study published in Nature Microbiology, researchers sought to explore how nutrient stress might affect drug-resistant bacteria. To do this, the team studied Klebsiella pneumoniae and Pseudomonas aeruginosa in a zinc-limited environment. Surprisingly, the researchers found that depriving the bacteria of zinc can cause physiological changes, rendering them increasingly vulnerable to antibiotics—including ones they previously resisted, like carbapenems.
Carbapenems are a last-resort antibiotics, clinically significant drugs that are used when everything else fails. Unfortunately, like other antibiotics, their efficacy is being threatened by resistance genes that have no clinically available solutions.
Under the zinc-limited conditions of the study, the researchers found that the bacteria’s ability to resist carbapenems through a common mechanism actually comes with a “trade-off.” Typically, resistant bacteria can simultaneously slice their way through the immune system while fending off antibiotics, like carbapenems.
However, when bacteria are deprived of zinc, they lose their strength and ability to do both. While the bacteria can still slash its way through incoming carbapenems, it loses the shield it once used to ward off antibiotics.
“[The bacteria are] still very deadly, but now it’s defenses are down,” said Brown.
Specifically, in the study, Brown and his team showed that both K. pneumoniae and P. aeruginosa were left wide open to azithromycin— one of the most commonly prescribed antibiotics in the world.
“Rather than identifying a novel drug candidate to treat these antibiotic-resistant infections, we’ve identified a trade-off that we can exploit using an existing drug,” said Megan Tu, a PhD candidate in Brown’s lab and first author on the new paper.
K. pneumoniae and P. aeruginosa are the “K” and “P” in “ESKAPE,” a globally recognized list of the six most deadly and drug-resistant bacterial pathogens. They are also both gram-negative bacteria, which are traditionally not affected by azithromycin. As such, the researchers say their study opens the door to new clinical utility for old drugs, while also cementing nutrient stress as a viable path to new treatments options for drug-resistant bacteria.
“Often, in this line of work, research can present more questions than answers—and that’s critically important for driving things forward,” Brown says. “But this study is one of those rare cases that actually culminates in resounding conclusion: you can treat certain drug-resistant Kleb and Pseudomonas infections with azithromycin.”