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Antibiotic tolerance facilitates the evolution of resistance

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Science  24 Feb 2017:
Vol. 355, Issue 6327, pp. 826-830
DOI: 10.1126/science.aaj2191

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Resistance on a background of tolerance

Bacteria survive antibiotic exposure either because they are quiescent when antibiotics are around in the highest concentrations (i.e., tolerance) or because they acquire active biochemical resistance mechanisms (i.e., resistance). Both tolerance and resistance involve the acquisition of mutations from the wild type. Levin-Reisman et al. used in vitro evolution experiments to show that populations of bacteria that become genetically resistant to the antibiotic ampicillin most quickly do so on a background of tolerance mutations (see the Perspective by Lewis and Shan). Because the probability of a tolerant organism surviving is higher, it has a greater chance of subsequently acquiring resistance mutations. Tolerance is often overlooked in the clinic but should in future be screened for and targeted more precisely to reduce the rates of acquired resistance.

Science, this issue p. 826; see also p. 796

Abstract

Controlled experimental evolution during antibiotic treatment can help to explain the processes leading to antibiotic resistance in bacteria. Recently, intermittent antibiotic exposures have been shown to lead rapidly to the evolution of tolerance—that is, the ability to survive under treatment without developing resistance. However, whether tolerance delays or promotes the eventual emergence of resistance is unclear. Here we used in vitro evolution experiments to explore this question. We found that in all cases, tolerance preceded resistance. A mathematical population-genetics model showed how tolerance boosts the chances for resistance mutations to spread in the population. Thus, tolerance mutations pave the way for the rapid subsequent evolution of resistance. Preventing the evolution of tolerance may offer a new strategy for delaying the emergence of resistance.

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