Potentiating antibiotics in drug-resistant clinical isolates via stimuli-activated superoxide generation

Courtney, Colleen M.; Goodman, Steven L.; Nagy, Toni A.; Levy, Max; Bhusal, Pallavi; Madinger, Nancy; Detweiler, Corrella S.; Nagpal, Prashant; Chatterjee, Anushree

doi:10.1126/sciadv.1701776

Cited by 116 publications

(137 citation statements)

References 38 publications

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“…Theoretically, low levels of ROS exist in bacteria during normal aerobic respiration, which can cause a series of bacterial biological responses and be mitigated by antioxidant defenses in bacteria, including superoxide dismutase (SOD) and catalase . However, the relative abundance of the local ROS concentration can destroy bacterial defenses and reduce enzyme activity, inducing apoptosis in the bacteria by oxidative stress . Compared with Ti‐RP/ZnO without bacteria, the 1 O 2 and •OH signal intensities of Ti‐RP/ZnO exposed to a S. aureus suspension decrease to 88% and 82%, respectively (Figure F).…”

Section: Resultsmentioning

confidence: 99%

“…However, the ESR peaks of 1 O 2 and •OH for Ti‐RP/ZnO exposed to an E. coli suspension intensify up to 107% and 128%, respectively. The difference between S. aureus and E. coli in the formation of 1 O 2 and •OH found in the ESR experiments is further confirmed using 2′,7′‐dicholorofluorescin diacetate (DCFH‐DA), where intracellular ROS stimulate the conversion of DCFH‐DA to a green fluorescent product (DCF) . As shown in Figure S13 (Supporting Information), Ti‐RP/ZnO group has the obviously stronger intensity of the intracellular ROS signal than that of Ti for S. aureus and E. coli due to the stronger intensity of fluorescent signal and the higher peak of absorption, exhibiting that ROS generated by Ti‐RP/ZnO under solar light leads to the increase of the intracellular ROS in bacteria.…”

Section: Resultsmentioning

confidence: 99%

“…Pathogenic microorganisms related to infectious diseases are the second largest murderer of death worldwide with 17 million annual victims . There is an increasing demand to explore innovative disinfection techniques in response to the prevalence of pathogenic microorganisms and bacterial outbreaks originating from medical treatment, contaminated water reservoirs, human contact, and so on . Specifically, medical device‐associated infections contribute to a great part of hospital‐acquired infections, which make up 25.6% of all health‐care‐associated infections in the USA .…”

Section: Introductionmentioning

confidence: 99%

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Light‐Activated Rapid Disinfection by Accelerated Charge Transfer in Red Phosphorus/ZnO Heterointerface

Liu²,

Liang

et al. 2019

Small Methods

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A red phosphorus (RP)/ZnO heterojunction thin film is developed to harvest solar or light emitting diode (LED) light for rapid, effective, ecofriendly, lower‐cost, and safe disinfection, which is convenient for universal and large‐scale deposition. The most stable geometrical structure of the RP/ZnO heterojunction, i.e., an RP (001) plane and a ZnO (002) plane, exhibits charge redistribution largely at the interface region. Therefore, the effective interfacial charge transfer and the improved separation efficiency of photogenerated electron–hole pairs can strongly boost reactive oxygen species (ROS)‐generation reactions to enhance photocatalytic bacterial inactivation. The excellent light‐activated point‐of use disinfection can be achieved even through LED light of phone. Additionally, the RP/ZnO heterojunction also possesses excellent solar light‐to‐heat conversion efficiency, leading to further lethality to bacteria through hyperthermia. Antibacterial efficacy of 99.96 ± 0.03% against Staphylococcus aureus at 5 min and 99.97 ± 0.02% against Escherichia coli at 4 min can be attributed to the synergetic antibacterial activity of solar photocatalysis and photothermal effect (more than 50 °C in 2 min). This platform provides a surface strategy for designing synergetic photocatalytic and photothermal materials to fully harvest solar energy for not only water disinfection but also antibacterial surfaces in medical facilities, touch screen devices, or seawater desalination.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Light‐Activated Rapid Disinfection by Accelerated Charge Transfer in Red Phosphorus/ZnO Heterointerface

Liu²,

Liang

et al. 2019

Small Methods

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“…Characterization of this isolate using the 2016–2017 Clinical & Laboratory Standards Institute (CLSI) sensitive/resistant breakpoint values 40 showed resistance to at least eight classes of antibiotics 41,42 . For this study, we tested the response of this strain to chloramphenicol as it exhibited greater than 8-fold higher MIC (>256 µg mL −1 ) than the corresponding CLSI breakpoint of 32 µg mL −1 (Supplementary Table 4).…”

Section: Resultsmentioning

confidence: 99%

Multiplexed deactivated CRISPR-Cas9 gene expression perturbations deter bacterial adaptation by inducing negative epistasis

et al. 2018

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The ever-increasing threat of multi-drug resistant bacteria, a shrinking antibiotic pipeline, and the innate ability of microorganisms to adapt necessitates long-term strategies to slow the evolution of antibiotic resistance. Here we develop an approach, dubbed Controlled Hindrance of Adaptation of OrganismS or CHAOS, involving induction of epistasis between gene perturbations to deter adaption. We construct a combinatorial library of multiplexed, deactivated CRISPR-Cas9 devices to systematically perturb gene expression in Escherichia coli. While individual perturbations improved fitness during antibiotic exposure, multiplexed perturbations caused large fitness loss in a significant epistatic fashion. Strains exhibiting epistasis adapted significantly more slowly over three to fourteen days, and loss in adaptive potential was shown to be sustainable. Finally, we show that multiplexed peptide nucleic acids increase the antibiotic susceptibility of clinically isolated Carbapenem-resistant E. coli in an epistatic fashion. Together, these results suggest a new therapeutic strategy for restricting the evolution of antibiotic resistance.

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“…5B). SL1344 is a model organism for studying bacteria in intracellular infections due to the relative ease in which it infects human cell lines (25). To explore the potential for gene expression perturbations to potentiate antibiotic efficacy in a therapeutic context, we created two new sgRNA plasmids: one harboring all six targets, and another harboring just the three with perfect homology.…”

Section: Crispri Potentiates Antibiotic Efficacy In Infection Modelsmentioning

confidence: 99%

Potentiating antibiotic treatment using fitness-neutral gene expression perturbations

Otoupal

Erickson

Eller

et al. 2019

Preprint

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The rapid proliferation of multidrug-resistant (MDR) bacteria poses a critical threat to human health, for which new antimicrobial strategies are desperately needed. Here we outline a strategy for combating bacterial infections by administering fitness neutral gene expression perturbations as co-therapies to potentiate antibiotic lethality. We systematically explored the fitness of 270 gene knockout-drug combinations in Escherichia coli, identifying 114 synergistic interactions. Genes revealed in this screen were subsequently perturbed at the transcriptome level via multiplexed CRISPR-dCas9 interference to induce antibiotic synergy. These perturbations successfully sensitized E. coli to antibiotic treatment without imposing a separate fitness cost. We next administered these fitness neutral gene perturbations as co-therapies to potentiate antibiotic killing of Salmonella enterica in intracellular infections of HeLa epithelial cells, demonstrating therapeutic applicability. Finally, we utilized these results to design peptide nucleic acid (PNA) co-therapies for targeted gene expression reduction in four MDR, clinically isolated bacteria. Two isolates of Klebsiella pneumoniae and E. coli were each exposed to PNAs targeting homologs of the genes csgD, fnr, recA and acrA in the presence of sub-minimal inhibitory concentrations of trimethoprim. We successfully increased each strain's susceptibility to trimethoprim treatment and identified eight cases in which re-sensitization occurred without a direct fitness impact of the PNA on MDR strains. Our results highlight a promising approach for combating MDR bacteria which could extend the utility of our current antibiotic arsenal.

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Potentiating antibiotics in drug-resistant clinical isolates via stimuli-activated superoxide generation

Abstract: Engineered nanoparticle for controlled superoxide flux potentiates antibiotics in MDR clinical isolates.

Cited by 116 publications

References 38 publications

Light‐Activated Rapid Disinfection by Accelerated Charge Transfer in Red Phosphorus/ZnO Heterointerface

Light‐Activated Rapid Disinfection by Accelerated Charge Transfer in Red Phosphorus/ZnO Heterointerface

Multiplexed deactivated CRISPR-Cas9 gene expression perturbations deter bacterial adaptation by inducing negative epistasis

Potentiating antibiotic treatment using fitness-neutral gene expression perturbations

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