The antibiotic scaffolds on which we all depend are getting more than a little rickety. Few new scaffolds have been found in decades. And the old scaffolds, which account for about 70% of clinical antibiotics in current use, may fold under the ever-heavier load of antibiotic resistance.

Finding new scaffolds is clearly a priority, but where are they hiding? Historically, they have been culled from the natural products of bacteria. To be more specific, most clinically used antibiotics have been derived from bacterial small molecules produced by dedicated biosynthetic gene clusters. It turns out that most of these clusters, perhaps 90% of them, remain unexplored. Accordingly, they have been dubbed silent, or even cryptic.

Awakening these silent gene clusters is crucial because they have great potential to produce drugs or drug-like molecules. Figuring out exactly how to do so, however, is challenging. Consider: An unknown signal activates an uncharacterized gene cluster leading to the production of a new metabolite.

To meet this challenge, a researcher at Princeton University, Mohammad Seyedsayamdost, Ph.D., has proposed a new strategy for awakening silent gene clusters using small molecule elicitors. Dr. Seyedsayamdost has described the strategy in a paper entitled “High-throughput platform for the discovery of elicitors of silent bacterial gene clusters,” which appeared in the May 20 issue of the Proceedings of the National Academy of Sciences.

“In this method, a genetic reporter construct affords a facile readout for activation of the silent cluster of interest, while high-throughput screening of small molecule libraries provides potential inducers,” wrote Dr. Seyedsayamdost.

This screening approach was applied to two cryptic gene clusters in the pathogenic model Burkholderia thailandensis. “Multiple elicitors for both clusters were discovered resulting in a 12–145-fold overproduction of their small molecule products, noted Dr. Seyedsayamdost. “Surprisingly, most elicitors were antibiotics, implicating a role for these compounds in activating secondary metabolism, when supplied at subinhibitory concentrations.”

“Turning these clusters on would really expand our available chemical space to search for new antibiotic or otherwise therapeutically useful molecules,” Dr. Seyedsayamdost said. In his article, he added that his study’s results “set the stage for understanding the regulatory cascades that induce silent gene clusters in response to exogenous elicitors and promise access to the extensive array of bioactive small molecules in bacterial cryptic metabolomes.”

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