Antibiotic tolerance facilitates the evolution of resistance.
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.
Racah Institute of Physics and the Harvey M. Kruger Family Center for Nanoscience and Nanotechnology, Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Irit
0000-0002-1565-3253
I
Levin-Reisman
Racah Institute of Physics and the Harvey M. Kruger Family Center for Nanoscience and Nanotechnology, Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Irine
I
Ronin
Racah Institute of Physics and the Harvey M. Kruger Family Center for Nanoscience and Nanotechnology, Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Orit
0000-0001-7638-4731
O
Gefen
Racah Institute of Physics and the Harvey M. Kruger Family Center for Nanoscience and Nanotechnology, Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Ilan
I
Braniss
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Noam
N
Shoresh
Racah Institute of Physics and the Harvey M. Kruger Family Center for Nanoscience and Nanotechnology, Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. nathalie.balaban@mail.huji.ac.il.
Nathalie Q
0000-0001-8018-0766
NQ
Balaban
D000667:Ampicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D019020:Directed Molecular Evolution; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D004361:Drug Tolerance; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D019143:Evolution, Molecular; D009154:Mutation; D011401:Promoter Regions, Genetic; D001618:beta-Lactamases / Q000235:genetics
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D000667:Ampicillin; C048795:AmpC beta-lactamases; D001618:beta-Lactamases