McMaster researchers have discovered a way to make deadly drug-resistant bacteria vulnerable to a commonly used antibiotic, opening the door to new utility for old drugs, and new treatment options for antibiotic-resistant infections.
Depriving bacteria of zinc can cause important physiological changes, rendering them increasingly vulnerable to antibiotics – including those they once resisted, researchers found in a study published in the journal Nature Microbiology.
“For the past hundred years or so, scientists have typically studied bacteria in the richest conditions imaginable,” says lead investigator Eric Brown, a professor in the department of Biochemistry and Biomedical Sciences. “My lab has had a longstanding interest in doing exactly the opposite: studying bacteria under nutrient stress.”
Zinc plays a vital role in how some of the world’s most dangerous bacteria resist antibiotics, the researchers found. Their study explored 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 first author Megan Tu, a PhD candidate in Brown’s lab.
“Unfortunately, like other antibiotics, their efficacy is being threatened by resistance genes that have no clinically available solutions.”
The researchers studied bacteria that resist carbapenems in zinc-limited environments and found that the bacteria’s ability to resist the drugs through a specific, common mechanism came with a “fitness cost” – or a trade-off.
Picture the bacteria as a knight holding a sword in one hand and a shield in the other, says Brown, a member of McMaster’s Michael G. DeGroote Institute for Infectious Disease Research.
Deprived of critical nutrients, like zinc, the knight loses the strength to hold both sword and shield, and must lay down the shield to hold the sword in both hands.
“It’s still very deadly, but now it defences are down,” he explains.
While it can still slash its way through incoming carbapenems, losing the shield creates new openings that other antibiotics can exploit.
In 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 are a type of bacteria called “gram-negatives,” which are not traditionally affected by azithromycin, Brown says.
The 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, the researchers say.
“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.”