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Web Date: March 6, 2017

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
Department: Science & Technology
News Channels: Biological SCENE
Keywords: infectious disease, multidrug resistances, pathogens, bacteria, Gram-negative
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Pentamidine helps disrupt the outer membrane of Gram-negative pathogens, allowing antibiotics inside to do their work.
Credit: Shutterstock
Cartoon of a Gram-negative bacteria membrance.
 
Pentamidine helps disrupt the outer membrane of Gram-negative pathogens, allowing antibiotics inside to do their work.
Credit: Shutterstock

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 multidrug 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 multidrug-resistant Gram-negative microbes from the Acinetobacter, Pseudomonas, and Enterobacteriaceae families. 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 patients by prescribing antibiotics that are toxic to nerve and kidney cells. But bacteria are even developing resistance to these suboptimal drugs, threatening “to cause a serious breach in our last line of defense against multidrug 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 typically use to kill the protozoan pathogens that cause sleeping sickness and leishmaniasis. After infecting mice with multidrug 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 exterior 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 U.S. Food & Drug Administration because it’s already been proven safe in humans.

The new work supports a growing belief among scientists that developing compounds to weaken bacteria, rather than kill them, 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.

 
Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society
Comments
Parthasarathi Das (Tue Mar 07 06:29:16 EST 2017)
Please find the documents
Fritiof Pontén (Thu Mar 09 01:54:35 EST 2017)
Very interesting observation and approach. QureTech Bio AB has a similar approach to Tuberculosis. The efficacy of Isoniazid is not only restored for Isoniazid resistant strains but is also boosted. The result is extremely effective killing of Mycobacteria tuberculosis.
Ayuk Eugene L. (Thu Mar 09 06:30:05 EST 2017)
Please can you give detail mechanism involved in the weakening of the membrane of the gram negative bacteria. Why are they more resistance than the gram positive ones. Can you describe a detail procedure for the synthesis of pentamidine? Don't you think derivatives of these pentadimine will do better jod than the parent drug?

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