Antibiotic treatment enhances the genome-wide mutation rate of target cells

Abstract

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.antibiotic resistance | mutation rate | resistance evolution | DNA repair | low-fidelity polymerases

Mutational Consequences of Ciprofloxacin in Escherichia coli

“…Additionally, it has been postulated that specifically 8-oxo-dG, particularly in the dGTP precursor, is the main DNA lesion responsible (40). Although we did not observe the mutational fingerprint of this lesion (A·T¡C·G) as a major part of the CPR-induced spectra in the targets studied here (see also the recent study by Long and coworkers [41]), clearly reactive oxygen species (ROS) are involved in CPR mutagenesis (42). Are the mutational spectra from different bactericidal antibiotics similar?…”

Whole-Genome Multilocus Sequence Typing of Extended-Spectrum-Beta-Lactamase-Producing Enterobacteriaceae

“…Estimates of the mutation and recombination rates of Enterobacteriaceae are limited and range from 0 to 10 mutations per genome per year (38,39). These rates reflect fixed substitution rates; short-term mutation (polymorphism) rates may be higher and are known to increase under antibiotic pressure or other environmental stress (40).…”

Intracellular d -Serine Accumulation Promotes Genetic Diversity via Modulated Induction of RecA in Enterohemorrhagic Escherichia coli

“…However, despite this apparent tolerance, expression of the SOS regulon persists, suggesting a mechanism of transcriptionally responding to this signal in order to quickly adapt to changing D-serine concentrations that may be encountered (31,41). Furthermore, SOS activation can lead to an increased mutational frequency and, in turn, increase bacterial fitness after exposure to even subinhibitory concentrations of antibiotics, for example (38,39,52). Indeed, one study reported that ciprofloxacin treatment of E. coli could increase the mutation frequency by a factor of 10 4 over the spontaneous rate (53).…”

“…In the UPEC ⌬dsdA mutant, D-serine accumulation also results in a higher recA induction than that of EHEC, suggesting that this stress may account for the apparent adaptation to D-serine tolerance in EHEC. Recent studies have suggested that antibiotic-mediated mutations can not only increase resistance to antibiotics but also generally enhance the fitness of the affected bacterial cells (39,52). It was also demonstrated that after rapid adaptation, SOS expression is actually decreased, limiting further unwanted mutagenic capability (52).…”

“…We previously demonstrated by transcriptome sequencing that multiple members of the SOS regulon were induced by D-serine accumulation in EHEC, including dinB, umuDC, and polB (31). The enzymes encoded by these genes are key members of the DNA repair process, but it is known that error-prone polymerase activity can lead to mutations in the population and that this can occur spontaneously in stationary phase or in response to antibiotic treatment, even at subinhibitory concentrations (38)(39)(40). We thus hypothesized that the SOS-like response induced by D-serine could be capable of promoting genetic diversity through this mechanism.…”