Antibiotic-Induced Mutagenesis: Under the Microscope

Revitt-Mills, Sarah A.; Robinson, Andrew

doi:10.3389/fmicb.2020.585175

Cited by 42 publications

(33 citation statements)

References 90 publications

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“…While the DNA replication process unavoidably causes spontaneous mutations during bacterial growth, the so-called "adaptive mutations" are induced by external stimuli and help bacteria to cope with stressful conditions [1,2]. One of these conditions is antibiotic exposure, which can increase the DNA mutation rate either by selecting cells with loss-of-function mutations in repair systems (hypermutator variants), or by directly promoting the expression and/or activity of error-prone DNA repair systems [3]. Antibiotic-induced mutagenesis is thought to be clinically important, as it can promote the emergence of resistant mutants during antibiotic treatment, thus contributing to the spread of drug resistance in bacterial pathogens [4,5].…”

Section: Introductionmentioning

confidence: 99%

RecA and Specialized Error-Prone DNA Polymerases Are Not Required for Mutagenesis and Antibiotic Resistance Induced by Fluoroquinolones in Pseudomonas aeruginosa

et al. 2022

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To cope with stressful conditions, including antibiotic exposure, bacteria activate the SOS response, a pathway that induces error-prone DNA repair and mutagenesis mechanisms. In most bacteria, the SOS response relies on the transcriptional repressor LexA and the co-protease RecA, the latter being also involved in homologous recombination. The role of the SOS response in stress- and antibiotic-induced mutagenesis has been characterized in detail in the model organism Escherichia coli. However, its effect on antibiotic resistance in the human pathogen Pseudomonas aeruginosa is less clear. Here, we analyzed a recA deletion mutant and confirmed, by conjugation and gene expression assays, that RecA is required for homologous recombination and SOS response induction in P. aeruginosa. MIC assays demonstrated that RecA affects P. aeruginosa resistance only towards fluoroquinolones and genotoxic agents. The comparison of antibiotic-resistant mutant frequency between treated and untreated cultures revealed that, among the antibiotics tested, only fluoroquinolones induced mutagenesis in P. aeruginosa. Notably, both RecA and error-prone DNA polymerases were found to be dispensable for this process. These data demonstrate that the SOS response is not required for antibiotic-induced mutagenesis in P. aeruginosa, suggesting that RecA inhibition is not a suitable strategy to target antibiotic-induced emergence of resistance in this pathogen.

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Section: Introductionmentioning

confidence: 99%

RecA and Specialized Error-Prone DNA Polymerases Are Not Required for Mutagenesis and Antibiotic Resistance Induced by Fluoroquinolones in Pseudomonas aeruginosa

et al. 2022

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“…Receptive proteins, due to their presence in the periplasmic spaces, form interactions with environmental polluters and may be susceptible through exposure to developing a system to remediate the anthropogenically magnified molecule. This is using the same fundamental reasoning as the acquisition of antibiotic resistance that is acquired through lateral transfer events as plasmid vectors, as well as due to mutations (due to increased evolvability) as a means to resist an antibiotic in the immediate medium, primarily through SOS mutagenesis where the microbes produce error-prone DNA polymerases [44]. Furthermore, endosymbionts change faster than free-living organisms due to genome erosion, pseudogenization, and stronger substitutions that are common in prototypical symbionts that have not yet become a full-fledged plastid [13].…”

Section: Discussionmentioning

confidence: 99%

A Hypothesis on How the Azolla Symbiosis Mitigates Nitrous Oxide Based on In Silico Analyses

Gunawardana

Herath

2022

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Nitrous oxide is a long-lived greenhouse gas that exists for 114 years in the atmosphere and is 298-fold more potent than carbon dioxide in its global warming potential. Two recent studies showcased the utility of Azolla plants for a lesser footprint in nitrous oxide production from urea and other supplements to the irrigated ecosystem, which mandates exploration since there is still no clear solution to nitrous oxide in paddy fields or in other ecosystems. Here, we propose a solution based on the evolution of a single cytochrome oxidase subunit II protein (WP_013192178.1) from the cyanobiont Trichormus azollae that we hypothesize to be able to quench nitrous oxide. First, we draw attention to a domain in the candidate protein that is emerging as a sensory periplasmic Y_Y_Y domain that is inferred to bind nitrous oxide. Secondly, we draw the phylogeny of the candidate protein showcasing the poor bootstrap support of its position in the wider clade showcasing its deviation from the core function. Thirdly, we show that the NtcA protein, the apical N-effecting transcription factor, can putatively bind to a promoter sequence of the gene coding for the candidate protein (WP_013192178.1), suggesting a function associated with heterocysts and N-metabolism. Our fourth point involves a string of histidines at the C-terminal extremity of the WP_013192178.1 protein that is missing on all other T. azollae cytochrome oxidase subunit II counterparts, suggesting that such histidines are perhaps involved in forming a Cu center. As the fifth point, we showcase a unique glycine-183 in a lengthy linker region containing multiple glycines that is absent in all proximal Nostocales cyanobacteria, which we predict to be a DNA binding residue. We propose a mechanism of action for the WP_013192178.1 protein based on our in silico analyses. In total, we hypothesize the incomplete and rapid conversion of a likely heterocystous cytochrome oxidase subunit II protein to an emerging nitrous oxide sensing/quenching subunit based on bioinformatics analyses and past literature, which can have repercussions to climate change and consequently, future human life.

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“…The potential for inhibitors of DNA replication to accelerate the development of genetic resistance through the induction of mutagenic repair pathways (Cirz et al, 2005;Barrett et al, 2019;Revitt-Mills and Robinson, 2020) is a valid and commonly cited concern that might partially explain the relative under-exploration of DNA metabolism as source of new antibacterial drug targets (Reiche et al, 2017;van Eijk et al, 2017). Our results suggest that GRS could offer an interesting exception: that is, in binding the β clamp at the site of interaction with the DnaE1 replicative DNA polymerase (Kling et al, 2015) as well as other DNA metabolizing proteins, including ImuB, GRS appears to possess an intrinsic protective mechanism against induced mutagenesis -blocking both ImuB-dependent mutasome recruitment to stalled replisomes and post-repair fixation of mutations by the replicative polymerase, DnaE1.…”

Section: Discussionmentioning

confidence: 99%

The mycobacterial mutasome: composition and recruitment in live cells

Gessner

Martin

Reiche

et al. 2021

Preprint

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A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded “mycobacterial mutasome” – minimally comprising DnaE2 polymerase and ImuA′ and ImuB accessory proteins – remain elusive. Following exposure of mycobacteria to DNA damaging agents, we observe that DnaE2 and ImuB co-localize with the DNA polymerase III β subunit (β clamp) in distinct intracellular foci. Notably, genetic inactivation of the mutasome in an imuBAAAAGG mutant containing a disrupted β clamp-binding motif abolishes ImuB-β clamp focus formation, a phenotype recapitulated pharmacologically by treating bacilli with griselimycin and in biochemical assays in which this β clamp-binding antibiotic collapses pre-formed ImuB-β clamp complexes. These observations establish the essentiality of the ImuB-β clamp interaction for mutagenic DNA repair in mycobacteria, identifying the mutasome as target for adjunctive therapeutics designed to protect anti-TB drugs against emerging resistance.

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Antibiotic-Induced Mutagenesis: Under the Microscope

Cited by 42 publications

References 90 publications

RecA and Specialized Error-Prone DNA Polymerases Are Not Required for Mutagenesis and Antibiotic Resistance Induced by Fluoroquinolones in Pseudomonas aeruginosa

RecA and Specialized Error-Prone DNA Polymerases Are Not Required for Mutagenesis and Antibiotic Resistance Induced by Fluoroquinolones in Pseudomonas aeruginosa

A Hypothesis on How the Azolla Symbiosis Mitigates Nitrous Oxide Based on In Silico Analyses

The mycobacterial mutasome: composition and recruitment in live cells

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