Antibiotic-Induced Genetic Variation: How It Arises and How It Can Be Prevented

Blázquez, Jesús; Rodríguez-Beltrán, Jerónimo; Matić, Ivan

doi:10.1146/annurev-micro-090817-062139

Cited by 88 publications

(98 citation statements)

References 167 publications

(159 reference statements)

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“…Since the discovery that subinhibitory concentrations of streptomycin increase mutagenesis rates, similar effect have been reported for numerous antibiotics targeting various functions (Davies, Gilbert, & Gorini, ; Kohanski, DePristo, & Collins, ). The mechanisms that stimulate mutagenesis are related to the generation of reactive oxygen species and the SOS response, which are induced by antibiotics and have been linked to accelerated accumulation of mutations and evolution (Blazquez, Rodriguez‐Beltran, & Matic, ; Matic, Rayssiguier, & Radman, ). Antibiotics can also accelerate horizontal gene transfer through conjugation both within and between species (Barr, Barr, Millar, & Lacey, ; Doucet‐Populaire, Trieu‐Cuot, Dosbaa, Andremont, & Courvalin, ).…”

Section: Non‐inhibitory Activitiesmentioning

confidence: 99%

On the possible ecological roles of antimicrobials

Pishchany

Kolter

2020

Molecular Microbiology

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The Introduction of antibiotics into the clinical use in the middle of the 20th century had a profound impact on modern medicine and human wellbeing. The contribution of these wonder molecules to public health and science is hard to overestimate. Much research has informed our understanding of antibiotic mechanisms of action and resistance at inhibitory concentrations in the lab and in the clinic. Antibiotics, however, are not a human invention as most of them are either natural products produced by soil microorganisms or semisynthetic derivatives of natural products. Because we use antibiotics to inhibit the bacterial growth, it is generally assumed that growth inhibition is also their primary ecological function in the environment. Nevertheless, multiple studies point to diverse nonlethal effects that are exhibited at lower levels of antibiotics. Here we review accumulating evidence of antibiosis and of alternative functions of antibiotics exhibited at subinhibitory concentrations. We also speculate on how these effects might alter phenotypes, fitness, and community composition of microbes in the context of the environment and suggest directions for future research.

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Section: Non‐inhibitory Activitiesmentioning

confidence: 99%

On the possible ecological roles of antimicrobials

Pishchany

Kolter

2020

Molecular Microbiology

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“…The scenario set by the data above is reminiscent of the picture described for sublethal concentrations of β-lactam antibiotics that cause ROS production and induce Pol IVdependent mutagenesis in a SOS-independent fashion (Gutierrez et al, 2013). Similarly to what we describe above, it has been proposed that mutagenesis induced by antibiotics activate RpoS via induction of the dinB gene along with a reduction of the DNA-replication fidelity by inhibiting the MMR system of E. coli (Blazquez et al, 2018). Such an effect involves SdsR, a RpoS-controlled small RNA and Hfq which is the RNA chaperone that facilitates the post-transcriptional regulation of mRNAs by sRNAs (Gutierrez et al, 2013).…”

Section: Resultsmentioning

confidence: 67%

“…The origin of such lethality is endogenous formation of reactive oxygen species (ROS) during the execution of the first step of the route by DNT dioxygenase. Since the ensuing oxidative stress is ultimately converted into DNA mutagenesis, we have argued that similarly to the scenario described for emergence of some antibiotic resistances (Blazquez et al, 2018), stressinduced DNA damage helps cells to diversify genetically and thus to exploring the solution space for improving DNT-metabolization (Perez-Pantoja et al, 2013).…”

Section: Introductionmentioning

confidence: 97%

Evolving metabolism of 2,4‐dinitrotoluene triggers SOS‐independent diversification of host cells

Akkaya

Nikel

Pérez‐Pantoja

2018

Environmental Microbiology

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Summary The molecular mechanisms behind the mutagenic effect of reactive oxygen species (ROS) released by defective metabolization of xenobiotic 2,4‐dinitrotoluene (DNT) by a still‐evolving degradation pathway were studied. To this end, the genes required for biodegradation of DNT from Burkholderia cepacia R34 were implanted in Escherichia coli and the effect of catabolizing the nitroaromatic compound monitored with stress‐related markers and reporters. Such a proxy of the naturally‐occurring scenario faithfully recreated the known accumulation of ROS caused by faulty metabolism of DNT and the ensuing onset of an intense mutagenesis regime. While ROS triggered an oxidative stress response, neither homologous recombination was stimulated nor the recA promoter activity increased during DNT catabolism. Analysis of single‐nucleotide changes occurring in rpoB during DNT degradation suggested a relaxation of DNA replication fidelity rather than direct damage to DNA. Mutants frequencies were determined in strains defective in either converting DNA damage into mutagenesis or mediating inhibition of mismatch repair through a general stress response. The results revealed that the mutagenic effect of ROS was largely SOS‐independent and stemmed instead from stress‐induced changes of rpoS functionality. Evolution of novel metabolic properties thus resembles the way sublethal antibiotic concentrations stimulate the appearance of novel resistance genes.

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“…The antibiotic‐producing microbe ensures its immunity by the simultaneous creation of a means to subvert the mechanism of its antibiotic. Over decades of time these existential immunity solutions have escaped by horizontal gene transfer, and the stress responses activated by antibiotics have effected mutations in the target that subvert the antibiotic mechanism . The result is antibiotic‐resistant bacteria.…”

Section: Introductionmentioning

confidence: 99%

Constructing and deconstructing the bacterial cell wall

Fisher

Mobashery

2019

Protein Science

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The history of modern medicine cannot be written apart from the history of the antibiotics. Antibiotics are cytotoxic secondary metabolites that are isolated from Nature. The antibacterial antibiotics disproportionately target bacterial protein structure that is distinct from eukaryotic protein structure, notably within the ribosome and within the pathways for bacterial cell‐wall biosynthesis (for which there is not a eukaryotic counterpart). This review focuses on a pre‐eminent class of antibiotics—the β‐lactams, exemplified by the penicillins and cephalosporins—from the perspective of the evolving mechanisms for bacterial resistance. The mechanism of action of the β‐lactams is bacterial cell‐wall destruction. In the monoderm (single membrane, Gram‐positive staining) pathogen Staphylococcus aureus the dominant resistance mechanism is expression of a β‐lactam‐unreactive transpeptidase enzyme that functions in cell‐wall construction. In the diderm (dual membrane, Gram‐negative staining) pathogen Pseudomonas aeruginosa a dominant resistance mechanism (among several) is expression of a hydrolytic enzyme that destroys the critical β‐lactam ring of the antibiotic. The key sensing mechanism used by P. aeruginosa is monitoring the molecular difference between cell‐wall construction and cell‐wall deconstruction. In both bacteria, the resistance pathways are manifested only when the bacteria detect the presence of β‐lactams. This review summarizes how the β‐lactams are sensed and how the resistance mechanisms are manifested, with the expectation that preventing these processes will be critical to future chemotherapeutic control of multidrug resistant bacteria.

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Antibiotic-Induced Genetic Variation: How It Arises and How It Can Be Prevented

Cited by 88 publications

References 167 publications

On the possible ecological roles of antimicrobials

On the possible ecological roles of antimicrobials

Evolving metabolism of 2,4‐dinitrotoluene triggers SOS‐independent diversification of host cells

Constructing and deconstructing the bacterial cell wall

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