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Routes of Resistance

Our focus on using antibiotics to kill bacteria has blinded us to their diverse functions in the organisms that make these chemicals

Robert L. Dorit

Off-Label Meaning

Researchers such as Fernando Baquero and Jose L. Martinez of the National Center for Biotechnology in Madrid, and Julian Davies of the University of British Columbia, among others, have begun to articulate a radically different perspective on the role played by the now-mislabeled “antibiotics.” Far from being just stone-cold killers, naturally occurring antibiotics appear to be part of the vocabulary of bacteria, words in the nuanced language of this world unseen by humans. Like language, antibiotics are capable of conveying multiple meanings to different recipients.

At sublethal concentrations, antibiotics can have profound and unexpected effects on surrounding cells. Several different antibiotics, when present at a small fraction (less than 1 percent) of their lethal concentration, coordinate the expression of whole sets of genes in bacteria that sense the antibiotic. These coordinated responses are not simply the molecular expression of panic (the aptly named “SOS response”) expected when an antibiotic is present. The signal may, for instance, induce Pseudomonas aeruginosa bacteria to develop into a bacterial biofilm—an architecturally complex, surface-bound conglomeration of cells—which, regrettably, makes bacteria much less sensitive to antibiotics in clinical settings. In another irony, low concentrations of antibiotic appear to upregulate the expression of a suite of genes responsible for increased virulence, in effect transforming a benign bacterium into a pathogen. These and other examples, in short, suggest that antibiotics may be far more than just toxic substances designed to kill all bacteria within range. And in the latest of many surprises, George M. Church of Harvard Medical School and his colleagues have isolated hundreds of soil bacteria able to subsist on antibiotics as their sole source of nutrition. This is not resistance but rather downright insolence, as these bacteria think of antibiotics not as threatening molecules, but instead as food.

Our ability to understand the origin and role of antibiotics has, in effect, been hindered by the uses to which we put them. In a fit of intellectual narcissism, we assume that if we use them in clinical settings to kill bacteria, that must be what they evolved for. However, when we recast them in a subtler role as agents of competition, and also as regulators and communicators in the bacterial world, we can view their lethal (and thus, for us, salutary) effects in a different light. It is when we administer doses of antibiotics that are orders of magnitude greater than those encountered in nature that a subtle, modulated signal is transformed into a deafening, and increasingly deadly, roar.

If antibiotics are part of the whispered conversations of the microbial world, what then should we make of antibiotic resistance? The last 65 years of clinical antibiotic use have exposed a dizzying array of mechanisms that bacteria use to survive the presence of toxic antibiotic concentrations. The diversity and complexity of these mechanisms—enzymes that chemically disable antibiotics, shape-shifting targets that prevent antibiotics from binding, complex pumps that eject the antibiotic from the target cell—have raised an obvious evolutionary question: Where do these mechanisms come from? Part of the answer, unsurprisingly, is self-defense. Many of the bacteria that produce antibiotics also harbor mechanisms that make themselves impervious to that antibiotic compound. In the case of the lethal protein antibiotics discussed previously, the bacteriocins, producer bacteria also synthesize a second protein that pairs up with the antibiotic, rendering it inactive until it reaches its target.

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