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The higBA-Type Toxin-Antitoxin System in IncC Plasmids Is a Mobilizable Ciprofloxacin-Inducible System.
Qi, Q, Kamruzzaman, M, Iredell, JR
mSphere. 2021;(3):e0042421
Abstract
A putative type II toxin-antitoxin (TA) module almost exclusively associated with conjugative IncC plasmids is homologous to the higBA family of TA systems found in chromosomes and plasmids of several species of bacteria. Despite the clinical significance and strong association with high-profile antimicrobial resistance (AMR) genes, the TA system of IncC plasmids remains largely uncharacterized. In this study, we present evidence that IncC plasmids encode a bona fide HigB-like toxin that strongly inhibits bacterial growth and results in cell elongation in Escherichia coli. IncC HigB toxin acts as a ribosome-dependent endoribonuclease that significantly reduces the transcript abundance of a subset of adenine-rich mRNA transcripts. A glycine residue at amino acid position 64 is highly conserved in HigB toxins from different bacterial species, and its replacement with valine (G64V) abolishes the toxicity and the mRNA cleavage activity of the IncC HigB toxin. The IncC plasmid higBA TA system functions as an effective addiction module that maintains plasmid stability in an antibiotic-free environment. This higBA addiction module is the only TA system that we identified in the IncC backbone and appears essential for the stable maintenance of IncC plasmids. We also observed that exposure to subinhibitory concentrations of ciprofloxacin, a DNA-damaging fluoroquinolone antibiotic, results in elevated higBA expression, which raises interesting questions about its regulatory mechanisms. A better understanding of this higBA-type TA module potentially allows for its subversion as part of an AMR eradication strategy. IMPORTANCE Toxin-antitoxin (TA) systems play vital roles in maintaining plasmids in bacteria. Plasmids with incompatibility group C are large plasmids that disseminate via conjugation and carry high-profile antibiotic resistance genes. We present experimental evidence that IncC plasmids carry a TA system that functions as an effective addiction module and maintains plasmid stability in an antibiotic-free environment. The toxin of IncC plasmids acts as an endoribonuclease that targets a subset of mRNA transcripts. Overexpressing the IncC toxin gene strongly inhibits bacterial growth and results in cell elongation in Escherichia coli hosts. We also identify a conserved amino acid residue in the toxin protein that is essential for its toxicity and show that the expression of this TA system is activated by a DNA-damaging antibiotic, ciprofloxacin. This mobile TA system may contribute to managing bacterial stress associated with DNA-damaging antibiotics.
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Antimicrobial activities evaluation and phytochemical screening of some selected medicinal plants: A possible alternative in the treatment of multidrug-resistant microbes.
Kebede, T, Gadisa, E, Tufa, A
PloS one. 2021;(3):e0249253
Abstract
BACKGROUND Four out of five individuals rely on traditional medicine for their primary healthcare needs. Medicinal plants are endowed with diverse bioactive compounds to treat multidrug-resistant (MDR) microbes. So far, a less thorough examination has been made in this regard. This study aimed to evaluate antimicrobial activity and phytochemical screening of selected medicinal plants against MDR microbes. METHODS In vitro experimental study was carried out to evaluate antimicrobial effects and phytochemical screening of Rumex abyssinicus, Cucumis pustulatus, Discopodium penninervium, Lippia adoensis, Euphorbia depauperata, Cirsium englerianum, and Polysphaeria aethiopica against MDR bacteria and fungi. Aqueous and 80% methanolic extraction methods were employed for extraction. The susceptibility test, minimum inhibitory concentration, and minimum bactericidal or fungicidal concentration were measured using disc diffusion or broth micro-dilution as per the CLSI protocols. RESULT The 80% methanolic extraction method was a preferred method to aqueous. The phytochemical constituents identified were alkaloids, flavonoids, saponins, phenolic, tannins, terpenoidss, and cardiac glycosides. The hydroalcoholic extract demonstrated an appreciable antimicrobial role against MDR microbes with an MIC value of 1.0-128.0μg/ml and 11-29mm inhibition zone (IZ) in diameter. Extracts obtained from C. englerianum and E. depauperata showed a significant IZ ranged of 26-29mm on MRSA and Streptococcus pyogenes. MDR E. coli and K. pneumoniae showed 12-25mm and 23-28mm IZ in diameter, respectively. T. mentagraphytes was susceptible to all tested extracts. Moreover, S. pyogenes and K. pneumoniae were found the most susceptible bacteria to C. englerianum. Cirsium englerianum, L. adoensis, D. penninervium, and R. abyssinicus demonstrated remarkable antifungal effect against C. albicans and T. mentagrophytes, while R. abyssinicus showed the leading antifungal effect with 32 to 64μg/ml MIC values. CONCLUSION The plant extracts have shown appreciable antimicrobial activities comparable to the currently prescribed modern drugs tested. Accordingly, further studies on clinical efficacy trial, safety, toxicity and affordability analyses have to be instigated promptly, so as to head to the final step to synthesize precursor molecules for new effective antimicrobials.
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A systematic review of implications, mechanisms, and stability of in vivo emergent resistance to colistin and tigecycline in Acinetobacter baumannii.
Karakonstantis, S
Journal of chemotherapy (Florence, Italy). 2021;(1):1-11
Abstract
The potential of A. baumannii for acquired resistance to last resort antibiotics (colistin and tigecycline) during treatment has important clinical implications, especially when dealing with patients failing to improve despite treatment with an active antimicrobial. However, the relevant literature remains scattered. Therefore, a systematic search was conducted in PubMed and Scopus. Several studies reported emergence of resistance to colistin or tigecycline during treatment, in most cases (86%) resulting in persistent or recurrent infections, especially in cases of emergent resistance without fitness cost. Lipopolysaccharide modification in the case of colistin and overexpression of efflux pumps in the case of tigecycline were the main mechanisms of resistance. Emergent colistin resistance is often associated with fitness cost which may result in re-emergence of the fitter and more virulent colistin susceptible strain after cessation of antibiotic pressure. Prospective studies are needed to determine the frequency of emergent resistance during treatment and its impact on patient outcomes.
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Novel Insights on MRGPRX2-Mediated Hypersensitivity to Neuromuscular Blocking Agents And Fluoroquinolones.
Elst, J, Maurer, M, Sabato, V, Faber, MA, Bridts, CH, Mertens, C, Van Houdt, M, Van Gasse, AL, van der Poorten, MM, De Puysseleyr, LP, et al
Frontiers in immunology. 2021;:668962
Abstract
Neuromuscular blocking agents (NMBAs) like atracurium and rocuronium as well as fluoroquinolones (FQs) cause mast cell-mediated anaphylaxis by activating Mas-related G protein-coupled receptor X2 (MRGPRX2), but many questions remain unanswered. Here, we address three of them, namely whether primary human mast cells show similar activation by these drugs as murine mast cells and mast cell lines, how sugammadex protects from atracurium-induced MRGPRX2-mediated mast cell activation, and why some but not all patients treated with rocuronium develop anaphylaxis. We used peripheral blood-derived cultured mast cells from healthy donors and patients, assessed mast cell activation and degranulation by quantifying intracellular calcium and CD63 expression, respectively, and made use of MRGPRX2-silencing, via electroporation with Dicer-substrate small interfering RNAs, and single cell flow cytometric analyses. Atracurium, ciprofloxacin, and levofloxacin activated and degranulated primary human mast cells, but only MRGPRX2-positive and not MRGPRX2-negative or -silenced mast cells. Sugammadex attenuated the atracurium-induced and MRGPRX2-mediated activation and degranulation of human mast cells by reducing free atracurium levels. The mast cells of patients with IgE-independent anaphylaxis to rocuronium were similar, in their MRGPRX2 expression and function, to those of patients with IgE-mediated anaphylaxis. These findings further improve our understanding of the role and relevance of MRGPRX2-driven mast cell activation in anaphylactic reactions to NMBAs and FQs and may help to improve their prediction, prevention, and treatment.
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A pilot study of cystic fibrosis exacerbation response phenotypes reveals contrasting serum and sputum iron trends.
Gifford, AH, Polineni, D, He, J, D'Amico, JL, Dorman, DB, Williams, MA, Nymon, AB, Balwan, A, Budden, T, Zuckerman, JB
Scientific reports. 2021;(1):4897
Abstract
The cystic fibrosis (CF) community seeks to explain heterogeneous outcomes of pulmonary exacerbation (PEX) treatment. Serum and sputum inflammatory mediators may identify people with CF (PwCF) at risk for suboptimal responses. However, lack of an established association between response phenotypes and these mediators limits clinical application. In this pilot study, we prospectively characterized treatment response phenotypes by assessing health-related quality-of-life (HRQoL) during PEX. We also measured lung function and iron-related biochemical parameters in serum and sputum. We classified subjects as sustained symptom-responders (SRs) or non-sustained symptom-responders (NSRs) based on the absence or presence, respectively, of worsened symptom scores after initial improvement. We used linear mixed models (LMMs) to determine whether trends in lung function, hematologic, serum, and sputum indices of inflammation differed between response cohorts. In 20 PwCF, we identified 10 SRs and 10 NSRs with no significant differences in lung function at PEX onset and treatment durations. SRs had better model-predicted trends in lung function than NSRs during PEX. Non-linear trends in serum and sputum iron levels significantly differed between SRs and NSRs. In adults with cystic fibrosis, PEX treatment response phenotypes may be correlated with distinctive trends in serum and sputum iron concentrations.
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Punica granatum as a Source of Natural Antioxidant and Antimicrobial Agent: A Comprehensive Review on Related Investigations.
Jalali, A, Kiafar, M, Seddigh, M, Zarshenas, MM
Current drug discovery technologies. 2021;(2):207-224
Abstract
BACKGROUND The consumption of natural antioxidants is increasing due to the demand and tendency to natural foods. Punica granatum L. [Punicaceae] is a fruit with various bioactive ingredients. The effectiveness of this plant has been proved against various disorders such as hyperglycemia, hyperlipidemia, blood coagulation, infections, cancer, and dentistry. Among them, there are numerous researches on antimicrobial and antioxidant properties. Subsequently, the present study aimed to compile a review of those properties to outline this herb as a possible natural antioxidant and preservative. METHODS Synchronically, keywords "Punica granatum" with antimicrobial, or antibacterial, antifungal, antiviral, antioxidant and radical scavenging were searched through "Scopus" database up to 31st September 2019. Papers focusing on agriculture, genetics, chemistry, and environmental sciences were excluded, and also related papers were collected. RESULTS Among 201 papers focusing on related activities, 111 papers have dealt with antioxidant activities focusing based on DPPH assay, 59 with antibacterial, on both gram+ and gram- bacteria, 24 with antifungal effects, mostly on Aspergillus niger and Candida albicans, and 7 papers with antiviral activities. There were about 50 papers focusing on in-vivo antioxidant activities of this plant. CONCLUSION Taken together, botanical parts of P. granatum have possessed notable radical scavenging and antimicrobial activities that, with these properties, this plant can be introduced as a natural, safe source of preservative and antioxidant. Accordingly, P. granatum can be applied as excipient with the aforementioned properties in the pharmaceutical and food industries.
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Behavioural interventions to address rational use of antibiotics in outpatient settings of low-income and lower-middle-income countries.
Nair, MM, Mahajan, R, Burza, S, Zeegers, MP
Tropical medicine & international health : TM & IH. 2021;(5):504-517
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Abstract
OBJECTIVES To explore the current evidence on interventions to influence antibiotic prescribing behaviour of health professionals in outpatient settings in low-income and lower-middle-income countries, an underrepresented area in the literature. METHODS The systematic review protocol for this study was registered in PROSPERO (CRD42020170504). We searched PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies relating to antibiotic prescribing of health professionals in outpatient settings in low-income and lower-middle-income countries. Behavioural interventions were classified as persuasive, enabling, restrictive, structural or bundle (mix of different interventions). In total, 3,514 abstracts were screened and 42 studies were selected for full-text review, with 13 studies included in the final narrative synthesis. RESULTS Of the 13 included studies, five were conducted in Vietnam, two in Sudan, two in Tanzania, two in India and two in Kenya. All studies were conducted in the outpatient or ambulatory setting: eight took place in primary health centres, two in private clinics and three in pharmacies. Our review found that enabling or educational interventions alone may not be sufficient to overcome the ingrained incentives to link revenue generation to sales of antibiotics, and hence, their inappropriate prescription or misuse. Bundle interventions appear to be very effective at changing prescription behaviour among healthcare providers, including drug sellers and pharmacists. CONCLUSIONS Multi-faceted bundle interventions that combine regulation enforcement with face-to-face education and peer influence may be more effective than educational interventions alone at curbing inappropriate antibiotic use.
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Adjunctive treatments for the management of septic shock - a narrative review of the current evidence.
Donovan, K, Shah, A, Day, J, McKechnie, SR
Anaesthesia. 2021;(9):1245-1258
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Abstract
Septic shock is a leading cause of death and morbidity worldwide. The cornerstones of management include prompt identification of sepsis, early initiation of antibiotic therapy, adequate fluid resuscitation and organ support. Over the past two decades, there have been considerable improvements in our understanding of the pathophysiology of sepsis and the host response, including regulation of inflammation, endothelial disruption and impaired immunity. This has offered opportunities for innovative adjunctive treatments such as vitamin C, corticosteroids and beta-blockers. Some of these approaches have shown promising results in early phase trials in humans, while others, such as corticosteroids, have been tested in large, international, multicentre randomised controlled trials. Contemporary guidelines make a weak recommendation for the use of corticosteroids to reduce mortality in sepsis and septic shock. Vitamin C, despite showing initial promise in observational studies, has so far not been shown to be clinically effective in randomised trials. Beta-blocker therapy may have beneficial cardiac and non-cardiac effects in septic shock, but there is currently insufficient evidence to recommend their use for this condition. The results of ongoing randomised trials are awaited. Crucial to reducing heterogeneity in the trials of new sepsis treatments will be the concept of enrichment, which refers to the purposive selection of patients with clinical and biological characteristics that are likely to be responsive to the intervention being tested.
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Antibiotics and the developing intestinal microbiome, metabolome and inflammatory environment in a randomized trial of preterm infants.
Russell, JT, Lauren Ruoss, J, de la Cruz, D, Li, N, Bazacliu, C, Patton, L, McKinley, KL, Garrett, TJ, Polin, RA, Triplett, EW, et al
Scientific reports. 2021;(1):1943
Abstract
Antibiotic use in neonates can have detrimental effects on the developing gut microbiome, increasing the risk of morbidity. A majority of preterm neonates receive antibiotics after birth without clear evidence to guide this practice. Here microbiome, metabolomic, and immune marker results from the routine early antibiotic use in symptomatic preterm Neonates (REASON) study are presented. The REASON study is the first trial to randomize symptomatic preterm neonates to receive or not receive antibiotics in the first 48 h after birth. Using 16S rRNA sequencing of stool samples collected longitudinally for 91 neonates, the effect of such antibiotic use on microbiome diversity is assessed. The results illustrate that type of nutrition shapes the early infant gut microbiome. By integrating data for the gut microbiome, stool metabolites, stool immune markers, and inferred metabolic pathways, an association was discovered between Veillonella and the neurotransmitter gamma-aminobutyric acid (GABA). These results suggest early antibiotic use may impact the gut-brain axis with the potential for consequences in early life development, a finding that needs to be validated in a larger cohort.Trial Registration This project is registered at clinicaltrials.gov under the name "Antibiotic 'Dysbiosis' in Preterm Infants" with trial number NCT02784821.
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Optimization for biogenic microbial synthesis of silver nanoparticles through response surface methodology, characterization, their antimicrobial, antioxidant, and catalytic potential.
Ibrahim, S, Ahmad, Z, Manzoor, MZ, Mujahid, M, Faheem, Z, Adnan, A
Scientific reports. 2021;(1):770
Abstract
Silver is a poisonous but precious heavy metal that has widespread application in various biomedical and environmental divisions. Wide-ranging usage of the metal has twisted severe environmental apprehensions. Henceforth there is a cumulative call for the progress of modest, low-cost and, the ecological method for remediation of silver. In the present study, Bacillus cereus was isolated from contaminated soil. Various experimental factors like the amount of AgNO3, inoculum size, temperature, time, and pH were improved by using central composite design (CCD) grounded on response surface methodology (RSM). Optimized values for AgNO3 (1 mM) 10 ml, inoculum size (Bacillus cereus) 8.7 ml, temperature 48.5 °C, time 69 h, and pH 9 showed in the form of optimized ramps. The formed nanoparticles stayed characterized by UV-visible spectrophotometer, Scanning Electron Microscopy, Fourier transform infra-red spectrometry, particle size analyzer, and X-ray diffraction. The particle size ranges from 5 to 7.06 nm with spherical form. The antimicrobial effectiveness of synthesized nanoparticles was tested contrary to five multidrug resistant microbial strains, Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, Salmonella enterica, Porteus mirabilis by disc diffusion method. The minimum inhibitory concentrations and minimum lethal concentrations were detected by the broth macro dilution method. 2,2-diphenyl-1-picrylhydrazyl-hydrate (DPPH) was used to check the free radical scavenging ability of biogenic silver nanoparticles. Similarly, anti-radical activity was checked by 2,2'-Azino-Bis-3-Ethylbenzothiazoline-6-Sulfonic Acid (ABTS) with varying time intervals. Catalytic potential of biosynthesized silver nanoparticles was also investigated.