Researchers at McMaster University have discovered a critical vulnerability in drug-resistant bacteria: zinc — or a lack thereof.
In a recent study, published in the journal Nature Microbiology , researchers found that zinc plays a vital role in how some of the world's most dangerous bacteria resist antibiotics.
Eric Brown , a professor in McMaster's Department of Biochemistry and Biomedical Sciences and lead investigator on the study, says depriving bacteria of certain nutrients can cause important physiological changes, rendering them increasingly vulnerable to antibiotics — including those they once 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."
For this particular study, researchers sought to explore how nutrient stress might illuminate new approaches to treating infections that are resistant to a class of important antibiotics called 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 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, a member of McMaster's Michael G. DeGroote Institute for Infectious Disease Research , suggests picturing a knight in armor — a sword in one hand and a shield in the other.
"That's the bacteria," he says.
When deprived of critical nutrients, like zinc, Brown says that the knight loses the strength it needs to hold both its sword and its shield, and therefore must lay down its shield so that it can hold its sword in both hands.
"It's still very deadly, but now it's defences are down," he explains.
While it can still slash its way through incoming carbapenems, Brown says that losing the shield it once used to ward off other antibiotics creates new openings in the bacteria that can be exploited.
And the researchers did just that.
Brown, Tu, and co. 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 says.
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 says 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 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."
