Researchers at McMaster University have discovered a vulnerability in drug-resistant bacteria: zinc—or a lack thereof. Depriving bacteria of certain nutrients can cause important physiological changes, rendering them vulnerable to antibiotics, including those they once resisted. This new study revealed that zinc plays a vital role in how some of the most dangerous bacteria resist antibiotics. It opens the door to new clinical utility for old drugs, while also cementing nutrient stress as a viable path to new treatment options for drug-resistant bacteria.
Their findings are published in Nature Microbiology in an article titled, “Exploiting the fitness cost of metallo-β-lactamase expression can overcome antibiotic resistance in bacterial pathogens.”
“Carbapenems are last-resort antibiotics for treating bacterial infections,” the researchers wrote. “The widespread acquisition of metallo-β-lactamases, such as VIM-2, contributes to the emergence of carbapenem-resistant pathogens, and currently, no metallo-β-lactamase inhibitors are available in the clinic. Here we show that bacteria expressing VIM-2 have impaired growth in zinc-deprived environments, including human serum and murine infection models. Using transcriptomic, genomic, and chemical probes, we identified molecular pathways critical for VIM-2 expression under zinc limitation. In particular, disruption of envelope stress response pathways reduced the growth of VIM-2-expressing bacteria in vitro and in vivo.”
“For the past hundred years or so, scientists have typically studied bacteria in the richest conditions imaginable,” said Eric Brown, PhD, a professor in McMaster’s Department of Biochemistry and Biomedical Sciences and lead investigator on the study. “My lab has had a longstanding interest in doing exactly the opposite: studying bacteria under nutrient stress.”
In the current study, the researchers sought to explore how nutrient stress might illuminate new approaches to treating infections that are resistant to carbapenems.
“Carbapenems are last-resort antibiotics—clinically significant drugs that are used when everything else fails,” explained Megan Tu, a PhD candidate in Brown’s lab and first author of the new paper. “Unfortunately, like other antibiotics, their efficacy is being threatened by resistance genes that have no clinically available solutions.”
To explore new vulnerabilities in the bugs that resist these drugs, the researchers studied them in zinc-limited environments. Under these conditions, they found that the bacteria’s ability to resist carbapenems through a specific, common mechanism came with a “fitness cost”—or a trade-off.
Brown suggested picturing a knight in armor—a sword in one hand and a shield in the other.
“That’s the bacteria,” he said.
When deprived of critical nutrients, like zinc, the knight loses the strength it needs to hold both its sword and shield and therefore must lay down its shield so that it can hold its sword in both hands, Brown explained.
“It’s still very deadly, but now its defenses are down,” he explained.
While it can still slash its way through incoming carbapenems, Brown said that losing the shield it once used to ward off other antibiotics creates new openings in the bacteria that can be exploited.
The researchers showed that, by resisting carbapenems in zinc-limited conditions, the bacteria left themselves 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,” Tu said.
This study focused specifically on the bacteria Klebsiella pneumoniae and Pseudomonas aeruginosa—the “K” and “P” in “ESKAPE,” a globally recognized list of the six most deadly and drug-resistant bacterial pathogens.
Interestingly, both bugs under study are a type of bacteria called “gram-negatives,” which Brown said are not traditionally affected by azithromycin. As such, the researchers believe that their study opens the door to new clinical utility for old drugs, while also cementing nutrient stress as a viable path to new treatment 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 said. “But this study is one of those rare cases that actually culminates in a resounding conclusion—you can treat certain drug-resistant Kleb and Pseudomonas infections with azithromycin.”
