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Targeting Quorum Sensing Could Lead To Evolution-Proof Antibiotics

Cell study suggests bacteria resistant to quorum-sensing blockers can’t gain upper hand

by Carmen Drahl
August 25, 2014 | A version of this story appeared in Volume 92, Issue 34

A colony of bacteria resistant to a quorum-sensing inhibitor (dark spot inside black box) is surrounded by a light blue halo of a digested fluorescent nutrient. Other colonies (light spots), if close enough to the halo, can ‘cheat’ and grab digested nutrients for themselves.
Credit: ACS Chem. Biol.
One colony of resistant bacteria (dark spot) is able to digest a fluorescent nutrient to produce a light-blue halo. Regular microbes (light spots) that are close by can grab enough of the nutrient to survive.

No matter how innovative the antibiotic, eventually, bacteria evolve to resist it. But a new study in cells suggests that by targeting certain bacterial networking behaviors, including the chemical communication known as quorum sensing, scientists might slow development of resistance (ACS Chem. Biol. 2014, DOI: 10.1021/cb5004288).

Traditional antibiotics wipe out large swaths of bacteria, leaving the playing field open for one or two resistant microbes to dominate. Researchers developing quorum-sensing inhibitors would like some reassurance that the resistance problem won’t hinder their efforts, says Helen E. Blackwell of the University of Wisconsin, Madison. Her graduate student Joseph P. Gerdt set up a competition between two strains of Pseudomonas aeruginosa, a notoriously antibiotic-resistant pathogen. One strain had its quorum-sensing system genetically inactivated to mimic what would happen with a potent quorum-sensing inhibitor. The other strain mimicked bacteria that are resistant to quorum-sensing inhibitors.

Gerdt then placed the strains in situations where they’d need an active quorum-sensing system to process nutrients. But when “resistant” microbes made up 1% or less of the total population, they failed to become the dominant strain. Blackwell suggests two possible reasons for this. One is that low levels of resistant microbes give off low levels of quorum-sensing signals. Without the necessary quorum to turn on nutrient-digesting genes, resistant microbes never gain an advantage. The second reason is that when resistant microbes do manage to break down nutrients, regular microbes can nab enough nutrients in cell cultures to survive, a behavior microbiologists call “cheating.”

“These types of experiments are critical as we move forward in trying to develop practical applications of quorum sensing,” says University of Washington microbiologist E. Peter Greenberg. However, despite many teams’ efforts, he notes, no quorum-sensing inhibitor is yet potent enough or specific enough to be a drug.

Blackwell says her team has recently developed its best quorum-sensing inhibitors yet and plans to run them through further tests before eventually attempting animal studies.



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