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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