Zinc Stress Exposes Vulnerabilities in Drug-Resistant Bacteria

McMaster University researchers have discovered that zinc deficiency is a critical vulnerability in drug-resistant bacteria.

According to a recent study that was published in the journal Nature Microbiology, zinc is essential for some of the most harmful bacteria in the world to withstand antibiotics.

The study's Lead Investigator, Eric Brown, a Professor in McMaster's Department of Biochemistry and Biomedical Sciences, claims that depriving bacteria of specific nutrients can result in significant physiological changes that make them more susceptible to antibiotics, including ones they previously resisted.

For the past hundred years or so, scientists have typically studied bacteria in the richest conditions imaginable. My lab has had a longstanding interest in doing exactly the opposite: studying bacteria under nutrient stress.”  

Eric Brown, Study Lead Investigator and Professor, McMaster University

The goal of this study was to investigate how nutrient stress might reveal novel strategies for treating infections that are resistant to carbapenems, a class of significant antibiotics.

Carbapenems are 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.” 

Megan Tu, PhD Candidate and Study First Author, McMaster University

To investigate new vulnerabilities in drug-resistant bacteria, researchers studied them in zinc-limited environments. They discovered that the bacteria’s common mechanism for resisting carbapenems incurred a "fitness cost" or trade-off under these conditions.

Imagine a knight in armor, with a sword in one hand and a shield in the other, states Brown, a member of McMaster's Michael G. DeGroote Institute for Infectious Disease Research.

“That is the bacteria,” he said.

According to Brown, the knight must put down its shield to hold its sword in both hands because it loses the strength necessary to hold both when it is deficient in vital nutrients like zinc.

“It is still very deadly, but now it is defenses are down,” he explained.   

Although it can still cut through incoming carbapenems, Brown claims that when the bacteria lose the barrier it once employed to protect itself from other antibiotics, it leaves new vulnerabilities that can be taken advantage of.

And that is exactly what the researchers did.

Brown, Tu, and colleagues demonstrated that the bacteria exposed themselves to azithromycin, one of the most widely used antibiotics worldwide, by fending off carbapenems in zinc-limited environments.

Tu said, “Rather than identifying a novel drug candidate to treat these antibiotic-resistant infections, we have identified a trade-off that we can exploit using an existing drug.” 

The bacteria Klebsiella pneumoniae and Pseudomonas aeruginosa, the “K” and “P” in “ESKAPE,” a list of the six most dangerous and drug-resistant bacterial pathogens, were the specific focus of this investigation.

It is interesting to note that both of the microbes being studied belong to a class of bacteria known as “gram-negatives,” which Brown claims are not typically impacted by azithromycin. Therefore, the researchers think their study confirms nutrient stress as a promising avenue for new treatment options for drug-resistant bacteria and opens the door to new clinical utility for old drugs.

Often, in this line of work, research can present more questions than answers and that is critically important for driving things forward. 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.”

Eric Brown, Study Lead Investigator and Professor, McMaster University