Abstract
The development of antibiotic resistance poses an increasing threat to global health. Understanding how resistance develops in bacteria is critical for the advancement of new strategies to combat antibiotic resistance. In the 1980s, it was discovered that certain antibiotics induce elevated rates of mutation in bacteria. From this, an “increased evolvability” hypothesis was proposed: antibiotic-induced mutagenesis increases the genetic diversity of bacterial populations, thereby increasing the rate at which bacteria develop antibiotic resistance. However, antibiotic-induced mutagenesis is one of multiple competing factors that act on bacterial populations exposed to antibiotics. Its relative importance in shaping evolutionary outcomes, including the development of antibiotic resistance, is likely to depend strongly on the conditions. Presently, there is no quantitative model that describes the relative contribution of antibiotic-induced mutagenesis to bacterial evolution. A far more complete understanding could be reached if we had access to technology that enabled us to study antibiotic-induced mutagenesis at the molecular-, cellular-, and population-levels simultaneously. Direct observations would, in principle, allow us to directly link molecular-level events with outcomes in individual cells and cell populations. In this review, we highlight microscopy studies which have allowed various aspects of antibiotic-induced mutagenesis to be directly visualized in individual cells for the first time. These studies have revealed new links between error-prone DNA polymerases and recombinational DNA repair, evidence of spatial regulation occurring during the SOS response, and enabled real-time readouts of mismatch and mutation rates. Further, we summarize the recent discovery of stochastic population fluctuations in cultures exposed to sub-inhibitory concentrations of bactericidal antibiotics and discuss the implications of this finding for the study of antibiotic-induced mutagenesis. The studies featured here demonstrate the potential of microscopy to provide direct observation of phenomena relevant to evolution under antibiotic-induced mutagenesis.
Highlights
Specialty section: This article was submitted to Antimicrobials, Resistance and Chemotherapy, a section of the journal Frontiers in Microbiology
In clinically relevant bacterial pathogens, resistance to most antibiotics is AIM: Under the Microscope acquired through lateral gene transfer; mutational resistance dominates in some circumstances
While microscopy cannot resolve all of the gaps in knowledge that remain open in the field of antibiotic-induced mutagenesis, the studies highlighted in the current review demonstrate the potential for enormous gains to be made
Summary
Before discussing the molecular mechanisms of antibiotic-induced mutagenesis, it is useful to consider the cellular context in which it takes place. Using a combination of microscopy and classical genetics approaches, the Rosenberg group recently demonstrated that ciprofloxacin-induced mutagenesis is ROS-dependent, and is driven by error-prone double-strand break repair (Pribis et al, 2019). Ciprofloxacin-induced mutagenesis was found to be dependent on genes encoding pols II, IV, and V (polB, dinB, and umuDC), double-strand break repair factors (recA, recB, and ruvC), the SOS response (mutagenesis was blocked in a lexA [Ind−] background), and the RpoS response (Figure 3E; the RpoS response is introduced in greater detail ). The Rosenberg study points to pol IV-dependent error-prone break repair occurring in a subset of high-ROS, RpoS-positive cells (Pribis et al, 2019), our imaging study showed that ciprofloxacin-induced pol IV foci formed in all cells (Henrikus et al, 2020). One would hypothesize that disruption of the RpoS response would prevent the down-regulation of MutS, leading to more efficient detection of mismatches and a corresponding increase in the number of MutL foci detected in cells treated with antibiotics
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
