Bacteria’s Kryptonite?

Disease-causing bacteria become more virulent when they form a slimy biofilm. Researchers have now synthesized a chemical that breaks through the microbial goo (J. Am. Chem. Soc., DOI: 10.1021/ja209836z). They hope the compound could render resistant bacteria vulnerable to annihilation by antibiotics.

When bacteria form a biofilm, they extrude polysaccharides and other molecules to weave a matrix that helps them adhere to surfaces, evade the immune system, and communicate. “The idea is to keep them out of that biofilm,” says Christian Melander of North Carolina State University. “They are 1,000-times more resilient in biofilms.”

Previous research by Thomas Wood of Texas A&M University suggested that indole, a smelly heterocyclic compound that microbes use to signal one another, inhibits biofilm production (BMC Microbiol. DOI: 10.1186/1471-2180-7-42). But to ward off biofilms, patients would have to take large amounts of the chemical to be effective, making it a bad drug candidate. Melander hypothesized that potent indole derivatives would shut down biofilm production at lower concentrations and could form therapeutic adjuncts to antibiotics.

Melander and his team started with desformylflustrabromine, which shares its core with indole. They grew Escherichia coli and Staphylococcus aureus in a broth laced with varying concentrations of the compound. The researchers monitored the bacteria’s growth rate with ultraviolet-visible spectroscopy. They quickly discovered that the compound was toxic to bacteria, slowing both species’ growth significantly. Somewhat counterintuitively, the researchers found the compound’s toxicity problematic. Melander explains that an ideal biofilm inhibitor would be nontoxic, because, without evolutionary pressure to avoid a deadly chemical, the bacteria shouldn’t develop resistance to them.

So the researchers chemically tweaked their indole derivative, making some 25 related compounds and testing each for toxicity and biofilm inhibition. They employed a standard biofilm assay, which involves growing bacteria in a well and then pouring out the well’s contents. Researchers then estimate the quantity of biofilm by dyeing any microbes left in the well and counting them using spectroscopy. The number of bacteria left clinging to the walls of the well will be proportional to the amount of biofilm present.

One nontoxic derivative stood out above the rest, leaving the fewest hangers-on in the well and exhibiting 10- to 100-times more biofilm inhibition than indole does in E. coli and 100- to 1,000-times more inhibition in S. aureus. Melander next wants to test biofilm inhibitors on bacterial communities that contain more than one species. By blocking biofilm formation in one species, they should be able to disrupt these communities, he says.

Wood, of Texas A&M, comments that Melander’s biofilm inhibitors “do seem to be very potent.” Wood thinks these inhibitors could also help researchers better understand how bacteria talk through indole signaling.