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The importance of the human microbiome in health may be the single most valuable development in our conception of the microbial world since Pasteur’s germ theory of the 1860s. Its implications for our understanding of health and pathogenesis are profound. Coupled with the revolution in diagnostics that we are now witnessing – a revolution that changes medicine from a science of symptoms to a science of causes – we cannot continue to develop antibiotics as we have for the past 80 years. Instead, we need to usher in a new conception of the role of antibiotics in treatment: away from single molecules that target broad phylogenetic spectra and towards targeted molecules that cripple the pathogen while leaving the rest of the microbiome largely intact.

Pathogenic bacteria resistant to many or all antibiotics already exist. With the decline in microbiological research at pharmaceutical companies, the high rate at which resistance has evolved and spread has demanded a novel approach to addressing this critical human health issue. In the present paper, we propose a new paradigm in antibiotic discovery and development, one that applies ecological and evolutionary theory to design antimicrobial drugs that are more difficult and/or more costly to resist. In essence, we propose to simply adopt the strategies invented and applied by bacteria for hundreds of millions of years. Our research focuses on bacteriocins, powerful biological weapons, and their use as alternative therapeutics in human health.

The complex networks of life are driven by the action of microbes, simultaneously synthesizing and consuming, moving metabolites and energy with relentless, tireless efficiency. Communities of microbes are deeply interdependent, and every bacterial species depends on one or more other species for survival. The consequences of this interdependence are profound, making cooperation and collaboration at least as important as competition in the shaping of bacterial communities. The ability to synthesize a toxic protein raises some vexing challenges not only for the target cells but for the producers themselves. How, after all, can a producer strain keep from becoming the victim of its own lethal weapon? It is because that the producing cell also synthesizes an immunity protein that binds tightly to the killing domain of the bacteriocin, rendering it temporarily inactive. This safety catch will remain on until the bacteriocin is safely inside its intended target cell. The delicate balance between producer cells and target cells plays out in a surprising minuet that has been likened to the childhood game of rock-paper-scissors. A bacteriocin-producing strain emerges and acts as "paper" in our game, defeating the sensitive strain as "paper" covers "rock." Eventually, no sensitive cells survive, and only bacteriocin producers rule. But the emergence of a resistant strain from within the producer population plays the role of “scissors.” Little by little, the population shifts from bacteriocin producers to resistant cells: scissors beats paper. Yet in the absence of producers, the cost of resistance is high and the benefits nonexistent.

Last year, some 50 million pounds of antibiotics were used in the United States, an amount that would correspond to roughly 5 ta blespoons?or 75 doses?of antibiotics per person. In fact, much of this antibi otic?as much as 70 percent by some estimates?is being used not to treat infections, but instead to promote food production, as antibiotics have become a key ingredient in the American food chain. We are, in short, marinating the living world in antibiotics. Against this backdrop, the emergence of antibiotic-resistant pathogenic bacte ria can hardly come as a surprise. Anti biotics, after all, are used to suppress and kill bacteria, and bacteria, like every other living thing, have no greater evo lutionary imperative than to stay alive. Our overuse of antibiotics methodi cally rewards any bacterium fortunate enough to carry a mutation that confers even slight resistance to the substance in its environment. The less-fortunate