Levin-Reisman I, Brauner A, Ronin I, Balaban NQ, et al.
Proceedings of the National Academy of Sciences of the United States of America. Date of publication 2019 Jul 16;volume 116(29):14734-14739.
1. Proc Natl Acad Sci U S A. 2019 Jul 16;116(29):14734-14739. doi:
10.1073/pnas.1906169116. Epub 2019 Jul 1.
Epistasis between antibiotic tolerance, persistence, and resistance mutations.
Levin-Reisman I(1)(2), Brauner A(1)(2), Ronin I(1)(2), Balaban NQ(3)(2).
Author information:
(1)Racah Institute of Physics, The Hebrew University of Jerusalem, 91904
Jerusalem, Israel.
(2)The Harvey M. Kruger Family Center for Nanoscience and Nanotechnology, The
Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
(3)Racah Institute of Physics, The Hebrew University of Jerusalem, 91904
Jerusalem, Israel; nathalie.balaban@mail.huji.ac.il.
Understanding the evolution of microorganisms under antibiotic treatments is a
burning issue. Typically, several resistance mutations can accumulate under
antibiotic treatment, and the way in which resistance mutations interact, i.e.,
epistasis, has been extensively studied. We recently showed that the evolution of
antibiotic resistance in Escherichia coli is facilitated by the early appearance
of tolerance mutations. In contrast to resistance, which reduces the
effectiveness of the drug concentration, tolerance increases resilience to
antibiotic treatment duration in a nonspecific way, for example when bacteria
transiently arrest their growth. Both result in increased survival under
antibiotics, but the interaction between resistance and tolerance mutations has
not been studied. Here, we extend our analysis to include the evolution of a
different type of tolerance and a different antibiotic class and measure
experimentally the epistasis between tolerance and resistance mutations. We
derive the expected model for the effect of tolerance and resistance mutations on
the dynamics of survival under antibiotic treatment. We find that the interaction
between resistance and tolerance mutations is synergistic in strains evolved
under intermittent antibiotic treatment. We extend our analysis to mutations that
result in antibiotic persistence, i.e., to tolerance that is conferred only on a
subpopulation of cells. We show that even when this population heterogeneity is
included in our analysis, a synergistic interaction between antibiotic
persistence and resistance mutations remains. We expect our general framework for
the epistasis in killing conditions to be relevant for other systems as well,
such as bacteria exposed to phages or cancer cells under treatment.
Copyright © 2019 the Author(s). Published by PNAS.
DOI: 10.1073/pnas.1906169116
PMCID: PMC6642377
PMID: 31262806 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest statement: N.Q.B. and B.R.L.
are coauthors on a Consensus Statement [Nature Rev. Microbiol. 17, 441–448 (2019)
doi: 10.1038/s41579-019-0196-3].
