Concentration gradients promote antibiotic resistance

Concentration gradients promote antibiotic resistance. To become resistant to an antibiotic a bacterium must end up with several favorable mutations. Acquiring them all is tough. If the drug concentration is too high, intermediate mutants won’t have enough competitive advantage to survive the drug. If the drug concentration is too low, the mutants will be overwhelmed by the much larger wild-type population before they can acquire the next mutation. Yet Mycobacterium tuberculosis, Neisseria gonorrhoeae, and other pathogenic bacteria continue to defy antibiotics. How? Rutger Hermsen, Barrett Deris, and Terence Hwa of the University of California, San Diego (UCSD), have proposed an answer. Their approach embodies two basic and plausible ideas: First, drug concentrations vary within a host; second, bacteria can move back and forth between zones of different concentration. Conceivably, bacteria, having acquired one favorable mutation in a zone of low concentration, could establish colonies in a zone of slightly higher concentration, where they could subsist—unlike their more numerous unmutated cousins. The mutants could go on to proliferate in the new zone without competition. If repeated, the process of range expansion and selection could engender full resistance. To assess that possibility, the UCSD team built a stochastic model in which the gradual acquisition of resistance depends on how readily each generation of bacteria mutates (favorably or unfavorably), proliferates, dies, or migrates to a new zone. Assigning plausible probabilities to those processes, the researchers found that their simulated bacteria did indeed acquire resistance—and rapidly. Their next step is to test the model in a microfluidic experiment. (R. Hermsen, J. B. Deris, T. Hwa, Proc. Natl. Acad. Sci. USA 109, 10775, 2012.)