Antibiotic treatment enhances the genome-wide mutation rate of target cells.
Although it is well known that microbial populations can respond adaptively to challenges from antibiotics, empirical difficulties in distinguishing the roles of de novo mutation and natural selection have left several issues unresolved. Here, we explore the mutational properties of Escherichia coli exposed to long-term sublethal levels of the antibiotic norfloxacin, using a mutation accumulation design combined with whole-genome sequencing of replicate lines. The genome-wide mutation rate significantly increases with norfloxacin concentration. This response is associated with enhanced expression of error-prone DNA polymerases and may also involve indirect effects of norfloxacin on DNA mismatch and oxidative-damage repair. Moreover, we find that acquisition of antibiotic resistance can be enhanced solely by accelerated mutagenesis, i.e., without direct involvement of selection. Our results suggest that antibiotics may generally enhance the mutation rates of target cells, thereby accelerating the rate of adaptation not only to the antibiotic itself but to additional challenges faced by invasive pathogens.
Department of Biology, Indiana University, Bloomington, IN 47405;
Hongan
H
Long
Department of Biology, Indiana University, Bloomington, IN 47405;
Samuel F
SF
Miller
Department of Biology, Indiana University, Bloomington, IN 47405;
Chloe
C
Strauss
Department of Biology, School of Life Sciences, East China Normal University, Shanghai, China 200241;
Chaoxian
C
Zhao
Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, Heilongjiang Province, China 150001;
Lei
L
Cheng
Department of Biology, Indiana University, Bloomington, IN 47405;
Zhiqiang
Z
Ye
Department of Biology, Indiana University, Bloomington, IN 47405;
Katherine
K
Griffin
Department of Biology, Indiana University, Bloomington, IN 47405;
Ronald
R
Te
School of Informatics and Computing, Indiana University, Bloomington, IN 47405.
Heewook
H
Lee
Department of Biology, Indiana University, Bloomington, IN 47405;
Chi-Chun
CC
Chen
Department of Biology, Indiana University, Bloomington, IN 47405; milynch@indiana.edu.
Michael
M
Lynch
D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics*; D019143:Evolution, Molecular; D016680:Genome, Bacterial / Q000187:drug effects / Q000235:genetics*; D042822:Genomic Instability / Q000187:drug effects / Q000235:genetics*; D016296:Mutagenesis / Q000187:drug effects / Q000235:genetics*; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D009643:Norfloxacin / Q000008:administration & dosage*
D000900:Anti-Bacterial Agents; D009643:Norfloxacin
DNA repair; antibiotic resistance; low-fidelity polymerases; mutation rate; resistance evolution