Researchers at McMaster University have identified a key weakness in drug-resistant bacteria: zinc—or the absence of it.
A recent study published in Nature Microbiology reveals that zinc is essential for some of the world’s most dangerous bacteria to withstand antibiotics.
Eric Brown, a professor in McMaster’s Department of Biochemistry and Biomedical Sciences and the study’s lead investigator, explains that depriving bacteria of specific nutrients triggers significant physiological changes, making them more susceptible to antibiotics they previously resisted.
“For the past hundred years or so, scientists have typically studied bacteria in the richest conditions imaginable,” Brown says. “My lab has had a longstanding interest in doing exactly the opposite: studying bacteria under nutrient stress.”
In this study, researchers investigated how nutrient stress could reveal new strategies for treating infections resistant to a crucial class of antibiotics known as carbapenems.
“Carbapenems are last-resort antibiotics — clinically significant drugs that are used when everything else fails,” says Megan Tu, a PhD candidate in Brown’s lab and first author on the new paper. “Unfortunately, like other antibiotics, their efficacy is being threatened by resistance genes that have no clinically available solutions.”
To uncover new weaknesses in drug-resistant bacteria, researchers examined them in zinc-limited environments. They discovered that under these conditions, the bacteria’s ability to resist carbapenems through a common mechanism came with a “fitness cost” or trade-off.
Brown, a member of McMaster’s Michael G. DeGroote Institute for Infectious Disease Research, likens this to a knight in armor—balancing a sword in one hand and a shield in the other.
“That’s the bacteria,” he says.
Brown explains that when deprived of essential nutrients like zinc, the knight becomes too weak to wield both a sword and a shield. As a result, it must drop the shield to grip the sword with both hands. “It’s still very deadly, but now it’s defenses are down,” he explains.
Though the bacteria can still cut through incoming carbapenems, Brown explains that losing the shield it once used to defend against other antibiotics leaves it vulnerable.
Seizing this opportunity, the researchers demonstrated that in zinc-limited conditions, bacteria that resisted carbapenems became highly susceptible to azithromycin—one of the world’s most widely prescribed antibiotics.
“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,” Tu says.
This study specifically examined Klebsiella pneumoniae and Pseudomonas aeruginosa—the “K” and “P” in ESKAPE, a globally recognized group of six highly drug-resistant and deadly bacterial pathogens.
Notably, both bacteria are classified as gram-negative, a type that is typically unaffected by azithromycin. However, Brown explains that their findings suggest a new clinical potential for existing drugs. The researchers believe this study not only highlights nutrient stress as a promising avenue for developing new treatments but also paves the way for repurposing older antibiotics to combat drug-resistant infections.
“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.”
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