The antibiotic resistome: the nexus of chemical and genetic diversity

Wright, Gerard D.

doi:10.1038/nrmicro1614

Cited by 1,117 publications

(876 citation statements)

References 97 publications

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“…Cultures were grown to an OD 600 of ∼1.2 before dilution to an OD 600 of 0.3 in LB containing indicated perturbations. H 2 O 2 dose responsiveness was assessed using freshly prepared H 2 O 2 dilutions made in dH 2 O from a stabilized 10-M stock solution (Sigma). At designated time points, samples were concentrated 10-fold in 1× PBS containing 50 μM Amplex UltraRed (Life Technologies) and were transferred to black, opaque-bottomed 96-well microplates.…”

Section: Methodsmentioning

confidence: 99%

“…reactive oxygen species | DNA repair | mutagenesis T he increasing incidence of antibiotic-resistant infections coupled with a declining antibiotic pipeline has created a global public health threat (1)(2)(3)(4)(5)(6). Therefore there is a pressing need to expand our conceptual understanding of how antibiotics act and to use insights gained from such efforts to enhance our antibiotic arsenal.…”

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confidence: 99%

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Antibiotics induce redox-related physiological alterations as part of their lethality

Dwyer

Belenky

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

737

683

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Deeper understanding of antibiotic-induced physiological responses is critical to identifying means for enhancing our current antibiotic arsenal. Bactericidal antibiotics with diverse targets have been hypothesized to kill bacteria, in part by inducing production of damaging reactive species. This notion has been supported by many groups but has been challenged recently. Here we robustly test the hypothesis using biochemical, enzymatic, and biophysical assays along with genetic and phenotypic experiments. We first used a novel intracellular H 2 O 2 sensor, together with a chemically diverse panel of fluorescent dyes sensitive to an array of reactive species to demonstrate that antibiotics broadly induce redox stress. Subsequent gene-expression analyses reveal that complex antibiotic-induced oxidative stress responses are distinct from canonical responses generated by supraphysiological levels of H 2 O 2 . We next developed a method to quantify cellular respiration dynamically and found that bactericidal antibiotics elevate oxygen consumption, indicating significant alterations to bacterial redox physiology. We further show that overexpression of catalase or DNA mismatch repair enzyme, MutS, and antioxidant pretreatment limit antibiotic lethality, indicating that reactive oxygen species causatively contribute to antibiotic killing. Critically, the killing efficacy of antibiotics was diminished under strict anaerobic conditions but could be enhanced by exposure to molecular oxygen or by the addition of alternative electron acceptors, indicating that environmental factors play a role in killing cells physiologically primed for death. This work provides direct evidence that, downstream of their target-specific interactions, bactericidal antibiotics induce complex redox alterations that contribute to cellular damage and death, thus supporting an evolving, expanded model of antibiotic lethality.reactive oxygen species | DNA repair | mutagenesis T he increasing incidence of antibiotic-resistant infections coupled with a declining antibiotic pipeline has created a global public health threat (1-6). Therefore there is a pressing need to expand our conceptual understanding of how antibiotics act and to use insights gained from such efforts to enhance our antibiotic arsenal. It has been proposed that different classes of bactericidal antibiotics, regardless of their drug-target interactions, generate varying levels of deleterious reactive oxygen species (ROS) that contribute to cell killing (7,8). This unanticipated notion, built upon important prior work (9-11), has been extended and supported by multiple laboratories investigating wide-ranging drug classes (e.g., β-lactams, aminoglycosides, and fluoroquinolones) and bacterial species (e.g., Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, Mycobacterium tuberculosis, Bacillus subtilis, Staphylococcus aureus, Acinetobacter baumannii, Burkholderia cepecia, Streptococcus pneumonia, Enterococcus faecalis) using independent lines of evidence (12-39). Importantly,...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Antibiotics induce redox-related physiological alterations as part of their lethality

Dwyer

Belenky

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

737

683

View full text Add to dashboard Cite

show abstract

“…Acquisition of exogenous genes by HGT can allow the recipient species to adapt rapidly to novel environments. This is very well known for species of medical interest that have acquired pathogenicity islands and antibiotic resistance genes through HGT (Hacker and Kaper, 2000;Hastings et al, 2004;Wright, 2007;Juhas et al, 2009). However, much less is known about microorganisms living in natural environments, especially those belonging to the domain Archaea.…”

Section: Introductionmentioning

confidence: 99%

Complete-fosmid and fosmid-end sequences reveal frequent horizontal gene transfers in marine uncultured planktonic archaea

et al. 2011

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The extent of horizontal gene transfer (HGT) among marine pelagic prokaryotes and the role that HGT may have played in their adaptation to this particular environment remain open questions. This is partly due to the paucity of cultured species and genomic information for many widespread groups of marine bacteria and archaea. Molecular studies have revealed a large diversity and relative abundance of marine planktonic archaea, in particular of Thaumarchaeota (also known as group I Crenarchaeota) and Euryarchaeota of groups II and III, but only one species (the thaumarchaeote Candidatus Nitrosopumilus maritimus) has been isolated in pure culture so far. Therefore, metagenomics remains the most powerful approach to study these environmental groups. To investigate the impact of HGT in marine archaea, we carried out detailed phylogenetic analyses of all open reading frames of 21 archaeal 16S rRNA gene-containing fosmids and, to extend our analysis to other genomic regions, also of fosmid-end sequences of 12 774 fosmids from three different deep-sea locations (South Atlantic and Adriatic Sea at 1000 m depth, and Ionian Sea at 3000 m depth). We found high HGT rates in both marine planktonic Thaumarchaeota and Euryarchaeota, with remarkable converging values estimated from complete-fosmid and fosmid-end sequence analysis (25 and 21% of the genes, respectively). Most HGTs came from bacterial donors (mainly from Proteobacteria, Firmicutes and Chloroflexi) but also from other archaea and eukaryotes. Phylogenetic analyses showed that in most cases HGTs are shared by several representatives of the studied groups, implying that they are ancient and have been conserved over relatively long evolutionary periods. This, together with the functions carried out by these acquired genes (mostly related to energy metabolism and transport of metabolites across membranes), suggests that HGT has played an important role in the adaptation of these archaea to the cold and nutrient-depleted deep marine environment.

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“…First, integrons are known to be crucial in the spread of antibiotic resistance in many human and animal pathogens (Hall et al, 1999). Second, integrons are especially prominent and well studied chromosomal elements in pathogenic and environmental Vibrio: indeed all sequenced Vibrio have at least one such integron array, often bearing more than 100 cassettes (reviewed in (Stokes and Hall, 1989;Rowe-Magnus et al, 2003;Wright, 2007)). Third, many species of Vibrio, such as V. shiloi and V. corallilyticus, are known or suspected coral pathogens and a role for Vibrio in bleaching can be inferred from an increasing proportion of Vibrio 16S rRNA genes sequenced during bleaching events .…”

Section: Introductionmentioning

confidence: 99%

Coral-mucus-associated Vibrio integrons in the Great Barrier Reef: genomic hotspots for environmental adaptation

et al. 2011

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Integron cassette arrays in a dozen cultivars of the most prevalent group of Vibrio isolates obtained from mucus expelled by a scleractinian coral (Pocillopora damicornis) colony living on the Great Barrier Reef were sequenced and compared. Although all cultivars showed 499% identity across recA, pyrH and rpoB genes, no two had more than 10% of their integron-associated gene cassettes in common, and some individuals shared cassettes exclusively with distantly-related members of the genus. Of cassettes shared within the population, a number appear to have been transferred between Vibrio isolates, as assessed by phylogenetic analysis. Prominent among the mucus Vibrio cassettes with potentially inferable functions are acetyltransferases, some with close similarity to known antibiotic-resistance determinants. A subset of these potential resistance cassettes were shared exclusively between the mucus Vibrio cultivars, Vibrio coral pathogens and human pathogens, thus illustrating a direct link between these microbial niches through exchange of integron-associated gene cassettes.

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The antibiotic resistome: the nexus of chemical and genetic diversity

Cited by 1,117 publications

References 97 publications

Antibiotics induce redox-related physiological alterations as part of their lethality

Antibiotics induce redox-related physiological alterations as part of their lethality

Complete-fosmid and fosmid-end sequences reveal frequent horizontal gene transfers in marine uncultured planktonic archaea

Coral-mucus-associated Vibrio integrons in the Great Barrier Reef: genomic hotspots for environmental adaptation

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