What counters antibiotic resistance in nature?

Antibiotics, which permit the effective treatment of bacterial infections, represent a fundamental triumph of medical science. However, their widespread clinical and agricultural use has led to the rapid emergence and spread of resistance. This proliferation of resistance reduces or eliminates the utility of antibiotics, rendering some clinical infections dangerously untreatable1. In light of the slow rate of discovery of new drugs, reducing the rate at which resistance evolves offers a tenable strategy for maintaining the efficacy of existing and future antibiotics1,2. To gain some insight into mechanisms that can keep antibiotic resistance in check, it is interesting to consider an evolutionary-ecological perspective. Most clinical antibiotics are derivatives of natural microbial products that evolved long before the era of medicinal antibiotic use and are commonly found in the chemical repertoire of soil microbes3–5. Resistance to these compounds evolved in the natural environment long ago, and in fact the resistance genes we see in the clinic today often bear similarity to genes in the environment3,6,7. Although the compounds and the resistance genes are similar in these two contexts, their dynamics are profoundly different. Whereas clinical resistance tends to increase substantially with time, resistant and sensitive bacteria have presumably existed together in soil environments for much longer periods (Fig. 1). Why is it that resistant bacteria do not take over in the soil environment? What mechanisms might be acting in nature to keep antibiotic resistance in check? We discuss several aspects of the soil environment that could explain why antibiotic resistance does not take over, including antibiotic combinations, compounds that inhibit or toxify resistance, degradation products of antibiotics and other ecological roles of antibiotics.