Specialized compounds that naturally reduce inflammation in mice also help clear bacterial infections. A combination of these inflammation-resolving factors and antibiotics lowers the antibiotic dose needed to clear E. coli and Staphylococcus, according to a new paper in Nature.
The finding suggests it would be possible to stimulate a person’s own defenses to enhance the effects of antibiotics—a potentially valuable weapon in the fight against increasing rates of antibiotic resistance.
“This paper bridges two seemingly different and distant areas of research—antimicrobial resistance and the resolution of inflammation,” said Alberto Mantovani, an immunologist at the University of Milan in Italy who was not involved in the research. “It’s an unexpected perspective.”
In the fight against antibiotic resistance, “a lot of efforts are focused on better, more effective antibiotics,” said Nan Chiang, an assistant professor at Brigham and Women’s and first author on the paper. “But we hope to address that problem from a different angle by stimulating a body’s own defenses” against pathogens, she said.
The resolution of an inflammatory response—after immune cells have gathered and responded to an injury—used to be considered a passive return to normal, as the immune cells dispersed in the absence of inflammatory stimulus. But in 2000, Charlie Serhan and colleagues at Brigham and Women’s Hospital at Harvard Medical School identified a class of fatty acid metabolites, dubbed “resolvins,” present in the tissues of mice that actively reduce inflammation, lowering the activity of pro-inflammatory cells while increasing the action of other cells that clear dead tissue. (For more, read our January feature, “Resolving Chronic Pain.”)
“Our general view of the resolution of inflammation has changed dramatically over the last few years,” said Mantovani. “Now we know resolution is an actively orchestrated process, which involves many different molecules.”
Recently, Serhan and Chiang decided to examine the role of resolvins and other specialized pro-resolving mediators (SPMs) in infection. In E. coli-infected mice, the researchers identified three SPMs: RvD5, RvD1, and PD1. Upon closer examination, they found that the three compounds heighten a mouse’s ability to fight infection, stimulating phagocytes to eat the invading E. coli and increasing survival time.
The researchers also looked at the effect of the SPMs in infected human white blood cells (WBCs). As in the mice, “we found they were able to stimulate WBCs to clear the bacteria,” said Chiang.
Given SPMs’ role in fighting infection, the team hypothesized that the compounds might improve antibiotic treatment by heightening a host’s antimicrobial response. They were right: administering SPMs and antibiotics together led to a faster resolution of the infection that either compound alone in infections of two types of bacteria, E. coli and Staphylococcus aureus. And the combination lowered the antibiotic dose needed to clear an infection.
“It proves the principle that you can treat the host to clear an infection,” said Chiang. Since humans, like mice, have natural SPMs, stimulating one’s own infection-resolving program could be a way to decrease the amounts of antibiotics needed in therapies, she said, thus decreasing the overall amount of antibiotics in use—often considered a cause of antibiotic resistance.
But Mantovani cautioned about the translational possibilities of the treatment from mice into humans. “It would be hard to think of a clinical trial in which you would actually use antibiotic treatment and add in with one of these compounds,” he said, since it wouldn’t be safe to reduce the antibiotic dosage of a person who has an infection just to test the combination of antibiotic and SPMs.
Still, he added, the study is valuable because it makes one consider the resolution of inflammation in a different way—not just as the final clearing of an infection but an active process that could be used against pathogens. “We should think about resolution also as a strategy to deliver the final hit to bugs,” he said.
N. Chiang, et al., “Infection regulates pro-resolving mediators that lower antibiotic requirements,” Nature, 484:524-8, 2012.