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Journal of Environmental Sciences... Apr 2024Antibiotic wastewater contains a variety of pollutant stressors that can induce and promote antibiotic resistance (AR) when released into the environment. Although these...
Antibiotic wastewater contains a variety of pollutant stressors that can induce and promote antibiotic resistance (AR) when released into the environment. Although these substances are mostly in concentrations lower than those known to induce AR individually, it is possible that antibiotic wastewater discharge might still promote the AR transmission risk via additive or synergistic effects. However, the comprehensive effect of antibiotic wastewater on AR development has rarely been evaluated, and its treatment efficiency remains unknown. Here, samples were collected from different stages of a cephalosporin production wastewater treatment plant, and the potential AR induction effect of their chemical mixtures was explored through the exposure of the antibiotic-sensitive Escherichia coli K12 strain. Incubation with raw cephalosporin production wastewater significantly promoted mutation rates (3.6 × 10-9.3 × 10-fold) and minimum inhibition concentrations (6.0-6.7-fold) of E. coli against ampicillin and chloramphenicol. This may be attributed to the inhibition effect and oxidative stress of cephalosporin wastewater on E. coli. The AR induction effect of cephalosporin wastewater decreased after the coagulation sedimentation treatment and was completely removed after the full treatment process. A Pearson correlation analysis revealed that the reduction in the AR induction effect had a strong positive correlation with the removal of organics and biological toxicity. This indicates that the antibiotic wastewater treatment had a collaborative processing effect of conventional pollutants, toxicity, and the AR induction effect. This study illustrates the potential AR transmission risk of antibiotic wastewater and highlights the need for its adequate treatment.
Topics: Wastewater; Anti-Bacterial Agents; Escherichia coli; Drug Resistance, Microbial; Cephalosporins; Monobactams
PubMed: 38135426
DOI: 10.1016/j.jes.2023.04.002 -
Journal of Global Antimicrobial... Mar 2024In-depth phenotypic and genomic analyses on a carbapenem-resistant Escherichia coli isolate, recovered from the faeces of a farm dog in Lebanon, focusing on its...
OBJECTIVES
In-depth phenotypic and genomic analyses on a carbapenem-resistant Escherichia coli isolate, recovered from the faeces of a farm dog in Lebanon, focusing on its antimicrobial resistance (AMR) patterns and the underlying resistome.
METHODS
E. coli strain EC-106 was identified using MALDI-TOF-MS. Analyses using Carba NP, immunochromatographic assay NG Carba5, and other antimicrobial susceptibility testing were performed. Whole-genome sequencing (WGS) using the Illumina technology and different software available at the Center of Genomic Epidemiology wwere used to predict the resistome, sequence type (ST), plasmid types, and virulence genes.
RESULTS
Susceptibility testing revealed that E. coli EC-106 was multi-drug resistant, including against newer antimicrobials such as imipenem-relebactam (MIC = 16 µg/mL), meropenem-vaborbactam (MIC = 16 µg/mL), and ceftazidime-avibactam (MIC > 32 µg/mL), but remained susceptible to aztreonam (MIC = 0.12 µg/mL), aztreonam-avibactam (MIC = 0.06 µg/mL), and cefiderocol (MIC = 0.5 µg/mL). WGS analyses showed that E. coli EC-106 carried 13 acquired resistance genes associated with resistance to β-lactams (bla and bla), aminoglycosides (aac(3)-IId, aph(3')-Ia, aadA1, and aadA2), tetracyclines (tetA), amphenicols (partial catA1), macrolides (mphA), sulphonamides (sul1 and sul3), trimethoprim (dfrA12), and quaternary ammonium compounds (partial qacE). The bla was located on an IncX3 plasmid. The isolate was predicted to be a human pathogen (92.9%) and belonged to ST1011.
CONCLUSION
To our knowledge, this is the first report of the detection of an IncX3 plasmid carrying the bla gene in animals in Lebanon, highlighting the severe AMR challenges in the country. Taken together, our current and previous findings suggest that bla might be spreading in different hosts and genetic backgrounds across clinical and non-clinical settings.
Topics: Dogs; Humans; Animals; Escherichia coli; Aztreonam; Farms; Escherichia coli Infections; Drug Resistance, Multiple, Bacterial; Plasmids; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases
PubMed: 38128725
DOI: 10.1016/j.jgar.2023.12.006 -
The Journal of Antibiotics Mar 2024Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for... (Review)
Review
Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for Gram-negative bacterial infections is widespread due to their ability to traverse outer membranes through porins to gain access to the periplasm and disrupt peptidoglycan synthesis. More recent members of the cephalosporin class are administered as last resort treatments for complicated urinary tract infections, MRSA, and other multi-drug resistant pathogens, such as Neisseria gonorrhoeae. Unfortunately, there has been a global increase in cephalosporin-resistant strains, heteroresistance to this drug class has been a topic of increasing concern, and tolerance and persistence are recognized as potential causes of cephalosporin treatment failure. In this review, we summarize the cephalosporin antibiotic class from discovery to their mechanisms of action, and discuss the causes of cephalosporin treatment failure, which include resistance, tolerance, and phenomena when those qualities are exhibited by only small subpopulations of bacterial cultures (heteroresistance and persistence). Further, we discuss how recent efforts with cephalosporin conjugates and combination treatments aim to reinvigorate this antibiotic class.
Topics: Humans; Cephalosporin Resistance; Anti-Bacterial Agents; Cephalosporins; Gram-Negative Bacterial Infections; Neisseria gonorrhoeae; Monobactams
PubMed: 38114565
DOI: 10.1038/s41429-023-00687-y -
Proceedings of the National Academy of... Dec 2023For degradation of β-lactam antibiotics pollution in waters, the strained β-lactam ring is the most toxic and resistant moiety to biodegrade and redox-chemically treat...
For degradation of β-lactam antibiotics pollution in waters, the strained β-lactam ring is the most toxic and resistant moiety to biodegrade and redox-chemically treat among their functional groups. Hydrolytically opening β-lactam ring with Lewis acid catalysts has long been recognized as a shortcut, but at room temperature, such hydrolysis is too slow to be deployed. Here, we found when Cu was immobilized on imine-linked COF (covalent organic framework) (Cu/Py-Bpy-COF, Cu load is 1.43 wt%), as-prepared composite can utilize the light irradiation (wavelength range simulated sunlight) to in situ heat anchored Cu Lewis acid sites through an excellent photothermal conversion to open the β-lactam ring followed by a desired full-decarboxylation of hydrolysates. Under 1 W/cm simulated sunlight, Cu/Py-Bpy-COF powders placed in a microfiltration membrane rapidly cause a temperature rising even to ~211.7 °C in 1 min. It can effectively hydrolyze common β-lactam antibiotics in waters and even antibiotics concentration is as high as 1 mM and it takes less than 10 min. Such photo-heating hydrolysis rate is ~24 times as high as under dark and ~2 times as high as Cu homogenous catalysis. Our strategy significantly decreases the interference from generally coexisting common organics in waters and potential toxicity concerns of residual carboxyl groups in hydrolysates and opens up an accessible way for the settlement of β-lactam antibiotics pollutants by the only energy source available, the sunlight.
Topics: beta Lactam Antibiotics; Hot Temperature; Catalytic Domain; Environmental Pollutants; Lewis Acids; Anti-Bacterial Agents; beta-Lactams; Monobactams
PubMed: 38109527
DOI: 10.1073/pnas.2302761120 -
European Journal of Clinical... Feb 2024To evaluate the different present and future therapeutic β-lactam/β-lactamase inhibitor (BL/BLI) alternatives, namely aztreonam-avibactam, imipenem-relebactam,...
PURPOSE
To evaluate the different present and future therapeutic β-lactam/β-lactamase inhibitor (BL/BLI) alternatives, namely aztreonam-avibactam, imipenem-relebactam, meropenem-vaborbactam, cefepime-zidebactam, cefepime-taniborbactam, meropenem-nacubactam, and sulbactam-durlobactam against clinical isolates showing reduced susceptibility or resistance to cefiderocol in Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa.
METHODS
MIC values of aztreonam, aztreonam-avibactam, cefepime, cefepime-taniborbactam, cefepime-zidebactam, imipenem, imipenem-relebactam, meropenem, meropenem-vaborbactam, meropenem-nacubactam, sulbactam-durlobactam, and cefiderocol combined with a BLI were determined for 67, 9, and 11 clinical Enterobacterales, P. aeruginosa or A. baumannii isolates, respectively, showing MIC values of cefiderocol being ≥1 mg/L. If unavailable, the respective β-lactam breakpoints according to EUCAST were used for BL/BLI combinations.
RESULTS
For Enterobacterales, the susceptibility rates for aztreonam, cefepime, imipenem, and meropenem were 7.5%, 0%, 10.4%, and 10.4%, respectively, while they were much higher for cefepime-zidebactam (91%), cefiderocol-zidebactam (91%), meropenem-nacubactam (71.6%), cefiderocol-nacubactam (74.6%), and cefiderocol-taniborbactam (76.1%), as expected. For P. aeruginosa isolates, the higher susceptibility rates were observed for imipenem-relebactam, cefiderocol-zidebactam, and meropenem-vaborbactam (56% for all combinations). For A. baumannii isolates, lower susceptibility rates were observed with commercially or under development BL/BLI combos; however, a high susceptibility rate (70%) was found for sulbactam-durlobactam and when cefiderocol was associated to some BLIs.
CONCLUSIONS
Zidebactam- and nacubactam-containing combinations showed a significant in vitro activity against multidrug-resistant Enterobacterales clinical isolates with reduced susceptibility to cefiderocol. On the other hand, imipenem-relebactam and meropenem-vaborbactam showed the highest susceptibility rates against P. aeruginosa isolates. Finally, sulbactam-durlobactam and cefiderocol combined with a BLI were the only effective options against A. baumannii tested isolates.
Topics: Humans; Cefiderocol; Meropenem; Cefepime; Aztreonam; Anti-Bacterial Agents; Cephalosporins; Imipenem; beta-Lactamase Inhibitors; Microbial Sensitivity Tests; beta-Lactamases; Carboxylic Acids; Piperidines; Lactams; Boronic Acids; Cyclooctanes; Azabicyclo Compounds; Borinic Acids
PubMed: 38095831
DOI: 10.1007/s10096-023-04732-4 -
PLoS Biology Dec 2023The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. Expression of the MCR-1 protein affects bacterial...
The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. Expression of the MCR-1 protein affects bacterial fitness and this cost correlates with lipid A perturbation. However, the exact molecular mechanism remains unclear. Here, we identified the MCR-1 M6 variant carrying two-point mutations that conferred co-resistance to β-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe disturbance in lipid A, resulting in up-regulation of L, D-transpeptidases (LDTs) pathway, which explains co-resistance to β-lactams. Moreover, we show that a lipid A loading pocket is localized at the linker domain of MCR-1 where these 2 mutations are located. This pocket governs colistin resistance and bacterial membrane permeability, and the mutated pocket in M6 enhances the binding affinity towards lipid A. Based on this new information, we also designed synthetic peptides derived from M6 that exhibit broad-spectrum antimicrobial activity, exposing a potential vulnerability that could be exploited for future antimicrobial drug design.
Topics: Humans; Colistin; Anti-Bacterial Agents; beta Lactam Antibiotics; Lipid A; Antimicrobial Peptides; Monobactams; Plasmids; Drug Resistance, Bacterial; Escherichia coli Proteins; Microbial Sensitivity Tests
PubMed: 38091366
DOI: 10.1371/journal.pbio.3002433 -
Nature Communications Dec 2023Antibiotic resistance of bacteria is considered one of the most alarming developments in modern medicine. While varied pathways for bacteria acquiring antibiotic...
Antibiotic resistance of bacteria is considered one of the most alarming developments in modern medicine. While varied pathways for bacteria acquiring antibiotic resistance have been identified, there still are open questions concerning the mechanisms underlying resistance. Here, we show that alpha phenol-soluble modulins (PSMαs), functional bacterial amyloids secreted by Staphylococcus aureus, catalyze hydrolysis of β-lactams, a prominent class of antibiotic compounds. Specifically, we show that PSMα2 and, particularly, PSMα3 catalyze hydrolysis of the amide-like bond of the four membered β-lactam ring of nitrocefin, an antibiotic β-lactam surrogate. Examination of the catalytic activities of several PSMα3 variants allowed mapping of the active sites on the amyloid fibrils' surface, specifically underscoring the key roles of the cross-α fibril organization, and the combined electrostatic and nucleophilic functions of the lysine arrays. Molecular dynamics simulations further illuminate the structural features of β-lactam association upon the fibril surface. Complementary experimental data underscore the generality of the functional amyloid-mediated catalytic phenomenon, demonstrating hydrolysis of clinically employed β-lactams by PSMα3 fibrils, and illustrating antibiotic degradation in actual S. aureus biofilms and live bacteria environments. Overall, this study unveils functional amyloids as catalytic agents inducing degradation of β-lactam antibiotics, underlying possible antibiotic resistance mechanisms associated with bacterial biofilms.
Topics: Humans; Staphylococcus aureus; beta Lactam Antibiotics; Anti-Bacterial Agents; Monobactams; beta-Lactams; Staphylococcal Infections; Bacteria
PubMed: 38081813
DOI: 10.1038/s41467-023-43624-1 -
BMC Microbiology Dec 2023Certain strains of probiotic bacteria can secret functional substances namely digestive enzymes and functional peptides to regulate physiological conditions such as...
Certain strains of probiotic bacteria can secret functional substances namely digestive enzymes and functional peptides to regulate physiological conditions such as digestion and anti-oxidation, which are often incorporated in industrial broiler chick production. However, few studies have detailed the action mechanisms and effects of these bacteria on regulating growth and anti-oxidation levels in broiler chickens. Ligilactobacillus salivarius is a strain of probiotic bacteria used as dietary supplement. In the present study, Ligilactobacillus salivarius was evaluated for its secreted digestive enzymes in vitro. To detailed evaluate the action mechanisms and effects of gastrointestinal tract (GIT) microbiota on alleviating anti-oxidation levels of broiler chickens through the gut-brain axis. Ligilactobacillus salivarius was cultured and supplemented in the food of broilers to evaluate the probiotic effect on growth and anti-oxidation by modulation of gut microbial composition and its functional metabolites using metagenomic and metabolomic assays. Biochemical results showed that Ligilactobacillus salivarius secreted digestive enzymes: protease, lipase, and amylase. Broiler chickens with Ligilactobacillus salivarius supplemented for 42 days, showed increased body weights, a reduced oxidative status, decreased malondialdehyde levels, and improved activities rates of total superoxide dismutase, glutathione peroxidase IIand IV improved. The microbial composition of caecum was more abundant than those broiler without probiotics supplementation, owing 400 of total number (489) of bacterial operational taxonomic units (OTU). The genera of Lactobacillus, Megamonas, Ruminoccoccaceae, Ruminococcus, Alistipes and Helicobacter shared the dominant proportion of Candidatus _Arthromitus compared with the control chickens. These functional bacteria genera assisted in the transportation and digestion of amino acids, carbohydrates, and ions, synthesis of cellular membranes, and anti-oxidation. Uncultured_organism_g_ Anaerosporobacter, Lactobacillus salivarius, uncultured_bacterium_g_ Ruminococcaceae_UCG-014, uncultured_bacterium_g_ Peptococcus were strongly and positively correlated with body growth performance and anti-oxidation. A metabonomic assay suggested that the secreted of gamma-aminobutyric acid and monobactam was metabolized according to the Kyoto Encyclopedia of Genes and Genomes analysis. In conclusion, Ligilactobacillus salivarius optimized microbial composition of the caecum and secreted functional peptides through gut-brain axis to improve the body growth and antioxidation of broiler chicken.
Topics: Animals; Ligilactobacillus salivarius; Chickens; Brain-Gut Axis; Animal Feed; Probiotics; Bacteria; Peptides
PubMed: 38071295
DOI: 10.1186/s12866-023-03135-x -
Chemosphere Feb 2024Recently, beta-lactam antibiotics have gained attention as significant contributors to public health and environmental issues due to their potential toxicity. Our study...
Recently, beta-lactam antibiotics have gained attention as significant contributors to public health and environmental issues due to their potential toxicity. Our study employed machine learning to develop a model for assessing the aquatic toxicity of beta-lactam antibiotics on zebrafish. Notably, aztreonam (AZT), a synthetic monobactam and a subclass of beta-lactam antibiotics, demonstrated developmental effects in zebrafish embryos comparable to cephalosporins, indicating a potential for toxicity. Using a systems toxicology-based approach, we identified apoptosis and metabolic disorders as the primary pathways affected by AZT and its impurity F exposure. During the administration of monobactams, we noted that ctsbb, nos2a, and dgat2, genes associated with apoptosis and the metabolic pathway, exhibited significant differential expression. Molecular docking studies were conducted to ascertain the binding affinity between monobactam compounds and their potential targets-Ctsbb, Nos2a, and Dgat2. Furthermore, our research revealed that monobactams influence pre-mRNA alternative splicing, resulting in disruptions in the expression of genes involved in hair cells, brain, spinal cord, and fin regeneration (e.g., krt4, krt5, krt17, cyt1). Notably, we observed a correlation between the levels of rpl3 and rps7 genes, both important ribosomal proteins, and the detected alternative splicing events. Overall, this study enhances our understanding of the toxicity of beta-lactam antibiotics in zebrafish by demonstrating the developmental effects of monobactams and uncovering the underlying mechanisms at the molecular level. It also identifies potential targets for further investigation into the mechanisms of toxicity and provides valuable insights for early assessment of biological toxicity associated with antibiotic pollutants.
Topics: Animals; beta Lactam Antibiotics; Zebrafish; Molecular Docking Simulation; Anti-Bacterial Agents; Monobactams; Aztreonam
PubMed: 38065262
DOI: 10.1016/j.chemosphere.2023.140884 -
Antimicrobial Agents and Chemotherapy Jan 2024Cefiderocol is a siderophore cephalosporin designed to target multi-drug-resistant Gram-negative bacteria. Previously, the emergence of cefiderocol non-susceptibility...
Cefiderocol is a siderophore cephalosporin designed to target multi-drug-resistant Gram-negative bacteria. Previously, the emergence of cefiderocol non-susceptibility has been associated with mutations in the chromosomal cephalosporinase (PDC) along with mutations in the PirA and PiuA/D TonB-dependent receptor pathways. Here, we report a clinical case of cefiderocol-resistant that emerged in a patient during treatment. This resistance was associated with mutations not previously reported, suggesting potential novel pathways to cefiderocol resistance.
Topics: Humans; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Microbial Sensitivity Tests; Monobactams; Pseudomonas aeruginosa; Pseudomonas Infections
PubMed: 38063509
DOI: 10.1128/aac.01009-23