When antibiotics turn toxic

Marchant, Jo

doi:10.1038/d41586-018-03267-5

Cited by 127 publications

(67 citation statements)

References 8 publications

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“…This finding could be advantageous clinically, as there is a small percentage of individuals who have adverse responses to fluoroquinolones. 35 Although fluoroquinolones remain safe for most people, the drugs are widely prescribed and can severely damage human cells, including altering the host microbiome. 36 In addition, the in vitro MIC assay is often a predictor of success for in vivo work.…”

Section: Discussionmentioning

confidence: 99%

Glycyrrhizin Use for Multi-Drug Resistant Pseudomonas aeruginosa: In Vitro and In Vivo Studies

Hazlett

Ekanayaka

McClellan

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.Our purpose was to test glycyrrhizin (GLY) effects and ciprofloxacin interactions on multidrug resistant (MDR) isolates of Pseudomonas aeruginosa in vitro and in vivo in a mouse model of keratitis. METHODS.A Hardy-disk tested antibiotic sensitivity of isolates MDR9 (nonocular) and B1045 (ocular). GLY MIC (both isolates) and ciprofloxacin was determined spectrophotometrically. A live/dead assay using confocal microscopy and plate count, tested GLY effects on bacterial permeabilization/viability. Proteomics profiled bacterial efflux pumps (MDR9 vs. PAO1); RT-PCR comparatively tested GLY effects on their mRNA expression levels. The activity of efflux pumps was tested using ethidium bromide (EB); and scanning electron microscopy (SEM) visualized the effects of GLY treatment of bacteria. A combination of GLY and ciprofloxacin was tested in C57BL/6 mice (begun 18 hours after infection) and disease scored, photographed and MPO and plate counts done.RESULTS. MDR9 was resistant to 6/12 and B1045 to 7/12 antibiotics (both to ciprofloxacin). MIC GLY for MDR9 was 40 mg/mL and 15 mg/mL for B1045. Ciprofloxacin MIC (32 lg/ mL) was reduced 2-fold to 16 lg/mL when ciprofloxacin and GLY were combined. GLY altered bacterial membrane permeability and reduced viability. Proteomics revealed increased efflux pumps in MDR9 versus PAO1; GLY reduced their mRNA expression levels and EB suggested decreased activity. In C57BL/6 mice, treatment with GLY and ciprofloxacin versus ciprofloxacin, significantly reduced clinical scores, plate count, and MPO.CONCLUSIONS. GLY decreases MDR by: altering bacterial parameters, including viability and efflux pump activity. In vivo, it increases the effectiveness of ciprofloxacin, reducing ocular disease, plate count, and MPO activity.

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Section: Discussionmentioning

confidence: 99%

Glycyrrhizin Use for Multi-Drug Resistant Pseudomonas aeruginosa: In Vitro and In Vivo Studies

Hazlett

Ekanayaka

McClellan

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Reports have indicated an effect of EOs on a decrease of energy acquisition following the sabotage of fungal mitochondria by enhanced accumulation of reactive oxygen species (ROS) [19,20]. Indeed, these findings are in line with some action modes of commercial antibiotics [21]. Accordingly, exploring novel targets could be an instrument for developing safer fungicides with fewer and mitigated side effects.The investigation of the interaction of fungal cells with antifungal EOs agents may provide a global analysis of cellular gene expression alteration upon treatment.…”

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confidence: 87%

Cuminal Inhibits Trichothecium roseum Growth by Triggering Cell Starvation: Transcriptome and Proteome Analysis

Zhang

et al. 2020

Microorganisms

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Trichothecium roseum is a harmful postharvest fungus causing serious damage, together with the secretion of insidious mycotoxins, on apples, melons, and other important fruits. Cuminal, a predominant component of Cuminum cyminum essential oil has proven to successfully inhibit the growth of T. roseum in vitro and in vivo. Electron microscopic observations revealed cuminal exposure impaired the fungal morphology and ultrastructure, particularly the plasmalemma. Transcriptome and proteome analysis was used to investigate the responses of T. roseum to exposure of cuminal. In total, 2825 differentially expressed transcripts (1516 up and 1309 down) and 225 differentially expressed proteins (90 up and 135 down) were determined. Overall, notable parts of these differentially expressed genes functionally belong to subcellular localities of the membrane system and cytosol, along with ribosomes, mitochondria and peroxisomes. According to the localization analysis and the biological annotation of these genes, carbohydrate and lipids metabolism, redox homeostasis, and asexual reproduction were among the most enriched gene ontology (GO) terms. Biological pathway enrichment analysis showed that lipids and amino acid degradation, ATP-binding cassette transporters, membrane reconstitution, mRNA surveillance pathway and peroxisome were elevated, whereas secondary metabolite biosynthesis, cell cycle, and glycolysis/gluconeogenesis were down regulated. Further integrated omics analysis showed that cuminal exposure first impaired the polarity of the cytoplasmic membrane and then triggered the reconstitution and dysfunction of fungal plasmalemma, resulting in handicapped nutrient procurement of the cells. Consequently, fungal cells showed starvation stress with limited carbohydrate metabolism, resulting a metabolic shift to catabolism of the cell's own components in response to the stress. Additionally, these predicaments brought about oxidative stress, which, in collaboration with the starvation, damaged certain critical organelles such as mitochondria. Such degeneration, accompanied by energy deficiency, suppressed the biosynthesis of essential proteins and inhibited fungal growth.fungicides to be used for postharvest treatment, reduced efficacy due to the emergence of pathogen resistance to these chemicals, and the growing public concerns over chemical residues in food and the environment have necessitated the seeking of alternative solutions to control the fungal spoilage and to guarantee food safety and consumer health [8].Essential oils (EOs), generally recognized as safe by the US Food and Drug Administration [9], are natural substances with established antimicrobial activities [10,11] and are a candidate instrument for controlling postharvest disease [12,13]. Nonetheless, this candidacy is compromised by the expensiveness of these natural substances due to their generally low yields. However, exploring their mode of actions is valuable to the development of novel alternatives.The multicomponent EOs attribute their mode of act...

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“…Notably, ciprofloxacin has an FDA black-box label arising from adverse human side effects on the nervous and musculoskeletal systems(31), yet has been used to treat Crohn's disease, a chronic gastrointestinal disorder, with a reasonable safety profile on the gastrointestinal tract though unclear efficacy (32). The mechanisms for effects of ciprofloxacin on human cells have implicated damage to mitochondrial DNA and alterations in DNA-modifying enzymes, but a clear picture has not emerged (31,33). Gene expression and phenotypic effects of on March 6, 2020 at MASS INST OF TECHNOLOGY http://aac.asm.org/ Downloaded from these antibiotics on human colon mucosal barrier cells will thus help illuminate whether additional off-target effects of these drugs exist and should be further studied.…”

Section: Introductionmentioning

confidence: 99%

Clostridioides difficile -Associated Antibiotics Alter Human Mucosal Barrier Functions by Microbiome-Independent Mechanisms

Kester

Brubaker

Velazquez

et al. 2020

Antimicrob Agents Chemother

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A clinically relevant risk factor for Clostridioides difficile-associated disease (CDAD) is recent antibiotic treatment. Although broad-spectrum antibiotics have been shown to disrupt the structure of the gut microbiota, some antibiotics appear to increase CDAD risk without being highly active against intestinal anaerobes, suggesting direct nonantimicrobial effects. We examined cell biological effects of antibiotic exposure that may be involved in bacterial pathogenesis using an in vitro germfree human colon epithelial culture model. We found a marked loss of mucosal barrier and immune function with exposure to the CDAD-associated antibiotics clindamycin and ciprofloxacin, distinct from the results of pretreatment with an antibiotic unassociated with CDAD, tigecycline, which did not reduce innate immune or mucosal barrier functions. Importantly, pretreatment with CDAD-associated antibiotics sensitized mucosal barriers to C. difficile toxin activity in primary cell-derived enteroid monolayers. These data implicate commensal-independent gut mucosal barrier changes in the increased risk of CDAD with specific antibiotics and warrant further studies in in vivo systems. We anticipate this work to suggest potential avenues of research for host-directed treatment and preventive therapies for CDAD.

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When antibiotics turn toxic

Cited by 127 publications

References 8 publications

Glycyrrhizin Use for Multi-Drug Resistant Pseudomonas aeruginosa: In Vitro and In Vivo Studies

Glycyrrhizin Use for Multi-Drug Resistant Pseudomonas aeruginosa: In Vitro and In Vivo Studies

Cuminal Inhibits Trichothecium roseum Growth by Triggering Cell Starvation: Transcriptome and Proteome Analysis

Clostridioides difficile -Associated Antibiotics Alter Human Mucosal Barrier Functions by Microbiome-Independent Mechanisms

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