Dysbiosis in the Development of Type I Diabetes and Associated Complications: From Mechanisms to Targeted Gut Microbes Manipulation Therapies

Publication history: Accepted - 8 March 2021; Published online - 9 March 2021Globally, we are facing a worrying increase in type 1 diabetes mellitus (T1DM) incidence, with onset at younger age shedding light on the need to better understand the mechanisms of disease and step-up prevention. Given its implication in immune system development and regulation of metabolism, there is no surprise that the gut microbiota is a possible culprit behind T1DM pathogenesis. Additionally, microbiota manipulation by probiotics, prebiotics, dietary factors and microbiota transplantation can all modulate early host–microbiota interactions by enabling beneficial microbes with protective potential for individuals with T1DM or at high risk of developing T1DM. In this review, we discuss the challenges and perspectives of translating microbiome data into clinical practice. Nevertheless, this progress will only be possible if we focus our interest on developing numerous longitudinal, multicenter, interventional and double-blind randomized clinical trials to confirm their efficacy and safety of these therapeutic approachesThis research was funded by UEFISCDI, project ID PN-III-P1-1.1-PD-2019-0499, grant number 224/2021

Wastewater treatment plants, an “escape gate” for ESCAPE pathogens

Antibiotics are an essential tool of modern medicine, contributing to significantly decreasing mortality and morbidity rates from infectious diseases. However, persistent misuse of these drugs has accelerated the evolution of antibiotic resistance, negatively impacting clinical practice. The environment contributes to both the evolution and transmission of resistance. From all anthropically polluted aquatic environments, wastewater treatment plants (WWTPs) are probably the main reservoirs of resistant pathogens. They should be regarded as critical control points for preventing or reducing the release of antibiotics, antibiotic-resistant bacteria (ARB), and antibiotic-resistance genes (ARGs) into the natural environment. This review focuses on the fate of the pathogens Enterococcus faecium, Staphylococcus aureus, Clostridium difficile, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae spp. (ESCAPE) in WWTPs. All ESCAPE pathogen species, including high-risk clones and resistance determinants to last-resort antibiotics such as carbapenems, colistin, and multi-drug resistance platforms, were detected in wastewater. The whole genome sequencing studies demonstrate the clonal relationships and dissemination of Gram-negative ESCAPE species into the wastewater via hospital effluents and the enrichment of virulence and resistance determinants of S. aureus and enterococci in WWTPs. Therefore, the efficiency of different wastewater treatment processes regarding the removal of clinically relevant ARB species and ARGs, as well as the influence of water quality factors on their performance, should be explored and monitored, along with the development of more effective treatments and appropriate indicators (ESCAPE bacteria and/or ARGs). This knowledge will allow the development of quality standards for point sources and effluents to consolidate the WWTP barrier role against the environmental and public health AR threats

Density functional theory molecular modeling and antimicrobial behaviour of selected 1,2,3,4,5,6,7,8-octahydroacridine-N(10)-oxides

International audienc

Resistance and Virulence Features of Bacteroides spp. Isolated from Abdominal Infections in Romanian Patients

Anaerobic bacteria are predominant residents of the normal microbiota of the skin and mucous membranes but are also known to be associated with a number of human infections including peritonitis, appendicitis, abscesses, ulcers and wound infections. Herein, we investigate the antibiotic resistance profiles as well as the genetic support of antibiotic resistance and virulence determinants of anaerobic bacteria isolated from intra-abdominal infections. The study was performed on 198 Romanian patients from which different clinical samples were taken intra-operatory and sent for microbiological analyses. From the total number of isolated strains, a subset of 75 Bacteroides spp. were selected and further investigated for antibiotic resistance and virulence features, at phenotypic and genetic level. Our results obtained through the analysis of a significant number of Bacteroides strains could shed light on the virulence potential and mechanisms by which anaerobic bacteria can cause endogenous infections

In Silico and In Vitro Assessment of Antimicrobial and Antibiofilm Activity of Some 1,3-Oxazole-Based Compounds and Their Isosteric Analogues

In this paper, we report on the antimicrobial activity assessment of 49 compounds previously synthesized as derivatives of alanine or phenylalanine that incorporate a 4-(4-X-phenylsulfonyl)phenyl fragment (X = H, Cl, or Br), namely 21 acyclic compounds (6 × N-acyl-α-amino acids, 1 × N-acyl-α-amino acid ester, and 14 × N-acyl-α-amino ketones) and 28 pentatomic heterocycles from the oxazole-based compound class (6 × 4H-1,3-oxazol-5-ones, 16 × 5-aryl-1,3-oxazoles, and 6 × ethyl 1,3-oxazol-5-yl carbonates). Both in silico and in vitro qualitative and quantitative assays were used to investigate the antimicrobial potential of these derivatives against planktonic and biofilm-embedded microbial strains. Some of the tested compounds showed promising antimicrobial and antibiofilm activity depending on their chemical scaffold and lipophilic character

Insights into the impact of manure on the environmental antibiotic residues and resistance pool.

The intensive use of antibiotics in the veterinary sector, linked to the application of manure-derived amendments in agriculture, translates into increased environmental levels of chemical residues, AR bacteria (ARB) and antibiotic resistance genes (ARG). The aim of this review was to evaluate the current evidence regarding the impact of animal farming and manure application on the antibiotic resistance pool in the environment. Several studies reported correlations between the prevalence of clinically relevant ARB and the amount and classes of antibiotics used in animal farming (high resistance rates being reported for medically important antibiotics such as penicillins, tetracyclines, sulfonamides and fluoroquinolones). However, the results are difficult to compare, due to the diversity of the used antimicrobials quantification techniques and to the different amounts and types of antibiotics, exhibiting various degradation times, given in animal feed in different countries. The soils fertilized with manure-derived products harbor a higher and chronic abundance of ARB, multiple ARG and an enriched associated mobilome, which is also sometimes seen in the crops grown on the amended soils. Different manure processing techniques have various efficiencies in the removal of antibiotic residues, ARB and ARGs, but there is only a small amount of data from commercial farms. The efficiency of sludge anaerobic digestion appears to be dependent on the microbial communities composition, the ARB/ARG and operating temperature (mesophilic vs. thermophilic conditions). Composting seems to reduce or eliminate most of antibiotics residues, enteric bacteria, ARB and different representative ARG in manure more rapidly and effectively than lagoon storage. Our review highlights that despite the body of research accumulated in the last years, there are still important knowledge gaps regarding the contribution of manure to the AMR emergence, accumulation, spread and risk of human exposure in countries with high clinical resistance rates. Land microbiome before and after manure application, efficiency of different manure treatment techniques in decreasing the AMR levels in the natural environments and along the food chain must be investigated in depth, covering different geographical regions and countries and using harmonized methodologies. The support of stakeholders is required for the development of specific best practices for prudent – cautious use of antibiotics on farm animals. The use of human reserve antibiotics in veterinary medicine and of unprescribed animal antimicrobials should be stopped and the use of antibiotics on farms must be limited. This integrated approach is needed to determine the optimal conditions for the removal of antibiotic residues, ARB and ARG, to formulate specific recommendations for livestock manure treatment, storage and handling procedures and to translate them into practical on-farm management decisions, to ultimately prevent exposure of human population

In Silico and In Vitro Experimental Studies of New Dibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)-oximes Designed as Potential Antimicrobial Agents

In a drug-repurposing-driven approach for speeding up the development of novel antimicrobial agents, this paper presents for the first time in the scientific literature the synthesis, physico-chemical characterization, in silico analysis, antimicrobial activity against bacterial and fungal strains in planktonic and biofilm growth state, as well as the in vitro cytotoxicity of some new 6,11-dihydrodibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)oximes. The structures of intermediary and final substances (compounds 7a–j) were confirmed by 1H-NMR, 13C-NMR and IR spectra, as well as by elemental analysis. The in silico bioinformatic and cheminformatic studies evidenced an optimal pharmacokinetic profile for the synthesized compounds 7a–j, characterized by an average lipophilic character predicting good cell membrane permeability and intestinal absorption; low maximum tolerated dose for humans; potassium channels encoded by the hERG I and II genes as potential targets and no carcinogenic effects. The obtained compounds exhibited a higher antimicrobial activity against the planktonic Gram-positive Staphylococcus aureus and Bacillus subtilis strains and the Candida albicans fungal strain. The obtained compounds also inhibited the ability of S. aureus, B. subtilis, Escherichia coli and C. albicans strains to colonize the inert substratum, accounting for their possible use as antibiofilm agents. All the active compounds exhibited low or acceptable cytotoxicity levels on the HCT8 cells, ensuring the potential use of these compounds for the development of new antimicrobial drugs with minimal side effects on the human cells and tissues

Synthesis, Characterization, and Biological Evaluation of Novel N-{4-[(4-Bromophenyl)sulfonyl]benzoyl}-L-valine Derivatives

In this article, we present the design and synthesis of novel compounds, containing in their molecules an L-valine residue and a 4-[(4-bromophenyl)sulfonyl]phenyl moiety, which belong to N-acyl-α-amino acids, 4H-1,3-oxazol-5-ones, 2-acylamino ketones, and 1,3-oxazoles chemotypes. The synthesized compounds were characterized through elemental analysis, MS, NMR, UV/VIS, and FTIR spectroscopic techniques, the data obtained being in accordance with the assigned structures. Their purities were verified by reversed-phase HPLC. The new compounds were tested for antimicrobial action against bacterial and fungal strains, for antioxidant activity by DPPH, ABTS, and ferric reducing power assays, and for toxicity on freshwater cladoceran Daphnia magna Straus. Furthermore, in silico studies were performed concerning the potential antimicrobial effect and toxicity. The results of antimicrobial activity, antioxidant effect, and toxicity assays, as well as of in silico analysis revealed a promising potential of N-{4-[(4-bromophenyl)sulfonyl]benzoyl}-L-valine and 2-{4-[(4-bromophenyl)sulfonyl]phenyl}-4-isopropyl-4H-1,3-oxazol-5-one for developing novel antimicrobial agents to fight Gram-positive pathogens, and particularly Enterococcus faecium biofilm-associated infections