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Biological Chemistry

Simple Molecules Block Bacterial Biofilms

Antimicrobials: Compounds thwart film formation by interrupting osmotic regulation in microbes

by Jyoti Madhusoodanan
October 14, 2014

CORRECTION: On Oct. 21, 2014, this story was corrected to explain that when antibiotics kill bacterial cells, they exert a selection pressure on the microbes to develop resistance.

During an infection, pathogenic bacteria can gang up to form biofilms—complex layers of bacterial cells and secreted metabolites—that are tough to eradicate with antibiotics. Researchers have proposed a new strategy to prevent these troublesome biofilms from forming: Use compounds that interfere with bacteria’s ability to regulate osmosis (ACS Sustainable Chem. Eng. 2014, DOI: 10.1021/sc500468a).

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Credit: Janice Haney Carr/CDC
Populations of bacteria such as Pseudomonas aeruginosa group together to form infectious biofilms. P. aeruginosa cells are typically 0.5–0.8 μm in length.
Colorized scanning electron micrograph of Pseudomonas aeruginosa bacteria.
Credit: Janice Haney Carr/CDC
Populations of bacteria such as Pseudomonas aeruginosa group together to form infectious biofilms. P. aeruginosa cells are typically 0.5–0.8 μm in length.

Bacterial biofilms can start problems when they form on surfaces inside the body. For example, films of Pseudomonas aeruginosa in the lungs can cause life-threatening complications in patients with cystic fibrosis. And implants and prosthetics that develop biofilms might require removal or replacement. Because free-living forms of the same bacteria may be less virulent and easier to treat, researchers have explored blocking biofilm formation with compounds other than antibiotics. A benefit of this approach is that, unlike antibiotics, these drugs would not exert strong selective pressure on bacteria to develop resistance.

Several researchers have focused the search for such antibiofilm chemicals on those that interfere with bacterial quorum sensing or iron metabolism. However, Shaoyi Jiang and colleagues at the University of Washington, Seattle, homed in on a cell’s need for osmotic regulation instead.

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Credit: ACS Sustainable Chem. Eng.
Ethylcholine can inhibit biofilm formation by Pseudomonas aeruginosa.
Structure of ethylcholine.
Credit: ACS Sustainable Chem. Eng.
Ethylcholine can inhibit biofilm formation by Pseudomonas aeruginosa.

When bacteria start to form a biofilm, they begin secreting polysaccharides, proteins, and other molecules to form an extracellular matrix. The high concentration of sugars and salts in that matrix increases the osmotic pressure on the cells. If unchecked, this would force the bacteria to pump out large amounts of water, threatening their viability. So to counter the osmotic pressure, the bacteria boost the concentration of small molecules called osmoprotectants inside their cytoplasm. Jiang and his colleagues synthesized analogs of osmoprotectants to find compounds that might interfere with osmotic regulation and prevent the formation of biofilms.

The researchers began their search for osmotic disruptors with a library of 19 compounds structurally analogous to glycine betaine, an osmoprotectant used by P. aeruginosa. Six of the chemicals are novel choline analogs synthesized in the lab, while the others are commercially available.

Several of the compounds inhibited the growth of lab-cultured P. aeruginosa biofilms. Ethylcholine was the most potent compound tested, reducing biofilm mass by about 70%. It also was the only one that exerted its effects without also decreasing bacterial growth, suggesting it might not spark resistance. In subsequent tests, treating P. aeruginosa biofilms with ethylcholine did not change the bacteria’s susceptibility to the antibiotics tobramycin, gentamycin, or nalidixic acid.

However, it’s unclear precisely how ethylcholine acts to interrupt osmotic regulation within the bacteria. In future work, Jiang hopes to elucidate the mechanisms and test additional compounds generated in combinatorial libraries.

Fred M. Ausubel of Harvard Medical School finds the results “interesting, but preliminary.” Most animal cells also rely on choline-based compounds for various functions, he says. So the researchers will need to test ethylcholine on human cells or in animals to look for possible undesirable side effects to healthy tissue.

Nonetheless, designing molecules that target osmotic regulation could find widespread applications in treating other pathogens, as well as in nonmedical applications, according to Matthew J. Wargo of the University of Vermont. Because these compounds are relatively inexpensive, he says, they could be used to prevent the growth of biofilms that threaten safety in the food industry or those that cause plant disease.

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