Dual therapy first weakens, then kills antibiotic-resistant pathogens

The drug pentamidine disrupts the outer membrane of Gram-negative bacteria, allowing antibiotics inside to finish the job

Sarah Everts, Chemical & Engineering News, Mar 9, 2017

Among the most nefarious human pathogens are bacteria with two sets of membranes protecting their innards. The doubled armor can prevent antibiotics from penetrating these so-called Gram-negative bacteria, and it can help them develop resistance to antibiotics. Now a team led by Eric Brown at McMaster University has found a way to weaken the outer membrane of Gram-negative microbes so that previously unusable drugs can penetrate and kill the pathogens - including several multi-drug-resistant strains (Nat. Microbiol. 2017, DOI: 10.1038/nmicrobiol.2017.28).

In late February, the World Health Organization published a list of our planet’s most problematic bacterial pathogens. The top three are multi-drug-resistant Gram-negative microbes from the Acinetobacter and Pseudomonas genera and Enterobacteriaceae family. They can cause life-threatening pneumonia or systemic infections, and patients are increasingly acquiring them in hospitals. As a last resort, doctors can treat infected people with antibiotics that are toxic to nerve and kidney cells. But bacteria are developing resistance to even these suboptimal drugs, threatening “to cause a serious breach in our last line of defense against multi-drug-resistant Gram-negative pathogens,” Brown explains.

To tackle this problem, Brown and colleagues looked for compounds that disrupt the outer membranes of Gram-negative bacteria. They found an existing drug, pentamidine, which doctors often use to kill the protozoan pathogens that cause sleeping sickness and leishmaniasis. After infecting mice with multi-drug-resistant Acinetobacter baumannii, the team could cure the animals by administering a combination of pentamidine and antibiotics for Gram-positive pathogens, bacteria with only one membrane.

“Pentamidine can breathe life into drugs we don’t usually use for Gram-negative infections because they wouldn’t have been able to cross the outer membrane,” comments Robert Hancock, a University of British Columbia microbiologist who characterized Gram-negative pathogens early in his career and now focuses on battling antibiotic resistance. “And another exciting thing is that pentamidine is already a drug,” he adds. So there’s a possibility it could be fast-tracked by regulatory agencies such as the Food & Drug Administration because it’s already been proved safe in humans.

The new work supports a growing belief among scientists that developing compounds to weaken rather than kill bacteria can lessen pathogens’ evolutionary drive to become resistant. Once weakened, the pathogens can be killed with a drug that wouldn’t otherwise work. “The idea,” Brown adds, “is to add an agent to take care of a resistance mechanism, or in this case, to get around intrinsic resistance.”

But to date, Brown says only one success story for this strategy in the clinic comes to mind: bacteria that are resistant to antibiotics with a β-lactam ring in their structure (a family of broad-spectrum drugs that includes penicillin). These antibiotic-resistant bacteria have enzymes that break down the ring structure. So doctors prescribe β-lactamase inhibitors - weakening agents - along with β-lactam antibiotics to kill the pathogens.

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