"Our magic bullets have far more peaceful uses in the wild," says Marvin Whiteley at the University of Texas at Austin, referring to natural substances with antimicrobial activities. "Many known antibiotics are gene modulators, not weapons, requiring us to challenge our preconceptions about their ecological roles." The "view of antibiotics as therapeutic weapons is so strongly entrenched in our experience that we've ignored the more important functions these ubiquitous small molecules have in nature," adds Julian Davies from the University of British Columbia in Vancouver, Canada. They and other microbiologists are reappraising what such molecules do in natural settings, where their signaling activities appear more important than killing their microbial neighbors.

"Whiteley's research supports this concept and makes a very compelling argument for taking a broader view of the roles low-molecular-weight compounds play in nature," continues Davies, who pioneered the view that the compounds we use in high concentrations as antibiotics exhibit very different biochemical properties at subinhibitory levels. "Bacteria are naturally gregarious, usually crowding together in huge, mixed-population communities that are both highly competitive and highly communicative. It seems reasonable that the small-moleculeproducing microbes living mainly in soil and never meeting up with human pathogens are using what we call antibiotics for something else entirely and, although we still need more experimental proof, an important part of that something else appears to be communication."

However, the notion that some bacterially generated molecules are strictly dedicated to communication is also unlikely, Whiteley asserts. "What we seem to have are poisons that signal, and signals that poison-a killing-signaling duality that could have important clinical applications. But only when we fully understand the nuances of their languages will we be able to decipher bacterial messages and manipulate them to our advantage."

Unraveling these biochemical languages with their "numerous dialects and words that have multiple meanings is a Herculean task," Davies says. "How can one even begin to comprehend a language spoken by correspondents that are largely unknown? And how can the correspondents be identified when 99% of them can't be grown in the solitary confinement of a lab?"

Nonetheless, bacterial communication, or quorum sensing (QS), is now a matter of intense research interest. "Bacteria chatter continuously, and their words are chemical," says Bonnie Bassler at Princeton University in Princeton, N.J. Her studies of Vibrio harveyi, a marine bacterium that lights up when quorum numbers of signal molecules are reached, provides a good example of this phenomenon.

"There is much more to QS than just direct information trafficking," Whiteley says. "Take Pseudomonas aeruginosa, which kills competing bacteria and hijacks their iron stores using its Pseudomonas quinolone signal (PQS) as a weapon." The ability to bind iron undoubtedly confers an additional advantage on this already formidable opportunist. PQS not only signals for higher expression of virulence genes, including those involved in iron homeostasis, it also appears to sequester iron, thereby increasing the bacterium's overall competitiveness, he points out. Furthermore, PQS moves between cells in outer membrane vesicles (OMVs), and P. aeruginosa cells depend on PQS synthesis to form OMVs. "Thus, PQS is not only a potent communication signal, it physically assists in the delivery of itself and other vesicular cargo, probably by altering the properties of bacterial cell membranes," he says.

Pseudomonads also secrete secondary metabolites called phenazines that are structurally related to PQS. Phenazines have long been studied as redox-active poisons, generating toxic by-products such as oxygen and hydrogen peroxide in anaerobic environments. "However, scratch the surface of a biofilm and there's an anaerobic world, similar in some important respects to conditions on Earth billions of years ago," says Dianne Newman of the Massachusetts Institute of Technology in Cambridge, Mass. Some microorganisms produce acylated phenazine compounds in subtoxic concentrations under anaerobic conditions. For example, they serve as important electron carriers in the membranes of some methanogenic archaea.

Phenazines likely arose in an oxygen-free world, and their "antibiotic" effect could reflect the geochemical conditions prevalent on Earth today, she says. Phenazines also act as electron shuttles for iron (III), aid in iron (II) acqui sition, modulate intracellular redox homeostasis, and play a pivotal role in biofilm development, dramatically affecting the morphology of multicellular communities, says Newman. Phenazines are much more than antibiotics, she stresses. "They profoundly affect the producing organism metabolically and developmentally."

"Having diffusible QS signals with far-reaching effects in distance and scope was undoubtedly as vital in a primordial world as it is today," says Whiteley, whose recent thoughts on this subject are summarized in the May 2009 Trends in Microbiology. "Then, like now, bacteria liked to gather in high-density populations-a safety-in-numbers strategy." As more species arose, the need to compete for metabolites and niches also grew. With time, QS molecules gained a wider role in community protection and nutrient scavenging-doing more than just interacting with regulatory proteins to change gene expression. However, the more peaceful activities of the small molecules that we simplistically call "antibiotics" are not being discovered as quickly as Davies would like. "There are not yet enough believers," he contends.

Marcia Stone

Marcia Stone is a science writer based in New York City. More of her work can be seen at http://www.mstoneworks.net.

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