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Metabolomic Study Leads to Natural Molecules Mediating Antibiotic Response

NEW YORK (GenomeWeb News) – In a study appearing online today in Nature, researchers from the US and Sweden report on molecules known as specialized pro-solving mediators, or SPMs, that appear to enhance the effects of antibiotics in mice.

Two SPMs — called resolvin D5, or RvD5, and protectin D1, or PD1 — were found through mass spectrometry-based metabolipidomic analyses in samples taken from mice infected with Escherichia coli. Indeed, the team's follow-up experiments illustrated that these fatty acid-based molecules, as well as another resolvin called RvD1, contribute to anti-inflammatory and antibacterial processes in mouse models and human cells.

When they provided SPMs to E. coli- or Staphylococcus aureus-infected mice being treated with ciprofloxacin or vancomycin antibiotics, respectively, researchers found that the naturally occurring molecules improved the animals' response to the drugs as well as their subsequent outcomes.

"Stimulation of targeted host resolution responses by pro-resolving mediators in conjunction with bacterial-directed antibiotics lowers the required antibiotic doses for bacterial clearance," senior author Charles Serhan, a researcher with Harvard Medical School and director of the Brigham and Women's Hospital's Experimental Therapeutics and Reperfusion Injury Center, and colleagues wrote.

That, in turn, suggests that it may be possible to find SPM-related strategies for using lower levels of antibiotics, they explained, perhaps helping to turn the tide on antibiotic resistance.

"One of the particularly exciting findings is that SPMs can enhance the effectiveness of antibiotics, potentially lowering the amount needed to treat infections and reducing the risk of bacteria developing resistance," National Institutes of Health researcher Richard Okita said in a statement.

Okita, who was not involved in the current study, directs the National Institute of General Medical Sciences' pharmacology, physiology, and biological chemistry division.

Although temporary inflammation can help host cells oust bacteria and other pathogens, prolonged inflammation can cause problems, including tissue damage, researchers explained.

Because previous studies indicated that SPMs are actively involved in helping host cells return to normal after such acute inflammatory events, the team decided to use a mouse model to look for SPMs in mice infected with E. coli, a common and sometimes deadly bacterial pathogen.

Using mass spec, the investigators did metabolipidomic analyses on exudate samples from E. coli-infected, looking at the sorts of fatty acid-based molecules that either induced inflammatory responses or acted to help bring inflammation to an end.

In samples from mice that had successfully combated their E. coli infections without treatment, the top two SPM candidates identified were RvD5 and PD1. Another resolvin, known as RvD1, also showed up in samples taken during the infection but generally disappeared more quickly than RvD5 and PD1.

Through a series of follow-up experiments, the researchers illustrated that all three of the molecules had features consistent with a proposed SPM functions.

For instance, both RvD1 and RvD5 helped curb E. coli levels in blood and other samples from infected mice, reducing the negative symptoms associated with the infection. Meanwhile, RvD1, RvD5, and PD1 spurred on the activity of human immune cells engulfing E. coli bacteria.

And whereas the team's array-based gene expression analyses uncovered a jump in the expression of inflammation-related genes when human macrophage cells were first exposed to E. coli, adding RvD5 to the mix reined in the levels of some of the inflammation-promoting genes.

Finally, in mice that were infected with E. coli or that had S. aureus-related skin infections, researchers reported, supplementing antibiotic treatment with SPMs seemed to increase antibiotic effectiveness and decrease the amount of time needed for the treatments to take effect — all without suppressing the animals' overall immune function.

"Anti-inflammatory agents are widely known to be immunosuppressive," senior author Serhan said in a statement. "Now we have naturally occurring molecular pathways in our bodies that work like these agents and stimulate bacterial containment and resolution of infections, but do not come with the side effect of being immunosuppressive."

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