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International Journal of Antimicrobial... Mar 2024Enterobacterales with carbapenemase-independent resistance to carbapenems are sometimes selected during therapy and, on rare occasions, cause outbreaks. Most have...
Enterobacterales with carbapenemase-independent resistance to carbapenems are sometimes selected during therapy and, on rare occasions, cause outbreaks. Most have extended-spectrum or AmpC β-lactamases, together with changes to permeability or penicillin-binding proteins (PBPs). Newer β-lactam-β-lactamase inhibitor combinations may present useful options for infections due to these organisms. Accordingly, Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing broth-microdilution was used to measure the minimum inhibitory concentrations (MICs) of ceftazidime/avibactam and aztreonam/avibactam for 51 carbapenemase-negative Enterobacterales with resistance or reduced susceptibility to carbapenems: genomic sequencing of the least-susceptible organisms was also undertaken. MICs of the two avibactam combinations cross-correlated closely, but with fewer MICs (2/51 vs. 10/51) exceeding 8+4 mg/L in the case of ceftazidime/avibactam. Raised MICs for Escherichia coli were associated with PBP3 inserts together with CMY-42 β-lactamase; correlates among Enterobacter cloacae complex isolates remain elusive, with AmpC and PBP3 sequences found to be species specific. In the case of Klebsiella spp., no MICs exceeding 2 mg/L were seen for either combination. It appears that these avibactam combinations have potential against Enterobacterales with carbapenemase-independent carbapenem resistance or reduced susceptibility, with ceftazidime/avibactam being more reliably active than aztreonam/avibactam.
Topics: Aztreonam; Ceftazidime; beta-Lactamases; Carbapenems; Escherichia coli; Bacterial Proteins; Azabicyclo Compounds
PubMed: 38176458
DOI: 10.1016/j.ijantimicag.2023.107081 -
Frontiers in Plant Science 2023Flowering time, plays a crucial role in tobacco ecological adaptation besides its substantial influence on tobacco production and leaf quality. Meanwhile, it is...
Flowering time, plays a crucial role in tobacco ecological adaptation besides its substantial influence on tobacco production and leaf quality. Meanwhile, it is sensitive to biotic or abiotic challenges. The plant hormones Gibberellins (GAs), controlling a number of metabolic processes, govern plants growth and development. In this study, we created a late flowering mutant through knocking out by CRISPR/Cas9. It took around 13.0 and 12.1 days longer to budding and flowering compared to wild type Honghuadajinyuan. Nearly all of the evaluated agronomic characters deteriorated in , showing slower growth and noticeably shorter and narrower leaves. We found that was more prevalent in flowers through quantitative reverse transcription PCR analysis. Transcriptome profiling detected 4449, 2147, and 4567 differently expressed genes at the budding, flowering, and mature stages, respectively. The KEGG pathway enrichment analysis identified the plant-pathogen interaction, plant hormone signal transduction pathway, and MAPK signaling pathway are the major clusters controlled by throughout the budding and flowering stages. Together with the abovementioned signaling pathway, biosynthesis of monobactam, metabolism of carbon, pentose, starch, and sucrose were enriched at the mature stage. Interestingly, 108 up- and 73 down- regulated DEGs, impairing sugar metabolism, diterpenoid biosynthesis, linoleic and alpha-linolenic acid metabolism pathway, were continuously detected accompanied with the development of . This was further evidenced by the decreasing content of GA metabolites such as GA4 and GA7, routine chemicals, alkaloids, amino acids, and organic acids Therefore, we discovered a novel tobacco flowering time gene and resolved its regulatory network, which will be beneficial to the improvement of tobacco varieties.
PubMed: 38162297
DOI: 10.3389/fpls.2023.1340039 -
European Journal of Clinical... Mar 2024Relebactam is a novel β-lactamase inhibitor, which, when combined with imipenem/cilastatin, is active against both class A and class C β-lactamases. To evaluate in...
PURPOSE
Relebactam is a novel β-lactamase inhibitor, which, when combined with imipenem/cilastatin, is active against both class A and class C β-lactamases. To evaluate in vitro antimicrobial activity of imipenem/relebactam against a collection of recent clinical isolates of carbapenem-non-susceptible P. aeruginosa and K. pneumoniae ST258 and ST512 KPC producers belonging to different lineages from hospitals in Southern Spain.
METHODS
Six hundred and seventy-eight isolates were tested: 265 K. pneumoniae (230 ST512/KPC-3 and 35 ST258/KPC-3) and 413 carbapenem-non-susceptible P. aeruginosa. Imipenem, piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, ceftolozane/tazobactam, meropenem, amikacin, ciprofloxacin, colistin, and ceftazidime/avibactam were used as comparators against P. aeruginosa. Against K. pneumoniae ceftazidime, cefepime, aztreonam, and ceftolozane/tazobactam were not tested, and tigecycline was studied instead. MICs were determined in duplicate by broth microdilution according to EUCAST guidelines.
RESULTS
Imipenem/relebactam displayed potent in vitro activity against both sequence types of KPC-3-producing K. pneumoniae. MIC and MIC values were 0.25 mg/L and 1 mg/L, respectively, with percent of susceptible isolates >97%. Only three K. pneumoniae ST512/KPC-3 isolates and one ST258/KPC-3 were resistant to imipenem/relebactam. Relebactam sensitized 98.5% of K. pneumoniae isolates resistant to imipenem. The activity of imipenem/relebactam against P. aeruginosa was moderate (susceptibility rate: 62.7%). Analysis of the acquired and mutational resistome of isolates with high levels of resistance to imipenem/relebactam has not shown a clear association between them.
CONCLUSION
Imipenem/relebactam showed excellent activity against K. pneumoniae KPC-3. The activity of imipenem/relebactam against imipenem-resistant P. aeruginosa was moderate.
Topics: Humans; Imipenem; Ceftazidime; Pseudomonas aeruginosa; Klebsiella pneumoniae; Cefepime; Aztreonam; Anti-Bacterial Agents; Pseudomonas Infections; Tazobactam; beta-Lactamases; Drug Combinations; Microbial Sensitivity Tests; Cephalosporins; Azabicyclo Compounds
PubMed: 38157139
DOI: 10.1007/s10096-023-04735-1 -
Journal of Global Antimicrobial... Mar 2024Metallo-β-lactamase (MBL)-producing Enterobacterales are a major challenge worldwide due to limited treatment options. Aztreonam-avibactam (ATM-AVI), which is under...
OBJECTIVES
Metallo-β-lactamase (MBL)-producing Enterobacterales are a major challenge worldwide due to limited treatment options. Aztreonam-avibactam (ATM-AVI), which is under clinical development, has shown activity against MBL-positive isolates. This study evaluated the prevalence of MBL producers and the nature of enzymes among a global collection of clinical isolates of Enterobacterales from the Antimicrobial Testing Leadership and Surveillance program (ATLAS) surveillance program (2016-2020), and the antimicrobial activity of ATM-AVI and comparators against this collection.
METHODS
Non-duplicate clinical isolates of Enterobacterales (N = 106 686) collected across 63 countries were analysed. Antimicrobial susceptibility was performed using broth microdilution. Minimum inhibitory concentrations (MICs) were interpreted using Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing breakpoints. Provisional pharmacokinetic/pharmacodynamic breakpoint of ≤8 mg/L was considered for ATM-AVI. β-lactamase genes were characterized by polymerase chain reaction and sequencing. The Cochran Armitage Trend test was used to determine significant trends in percentage of isolates over time.
RESULTS
Overall, MBL-positive isolates were 1.6% of total Enterobacterales isolates globally, with a significant increasing trend observed over time, globally and across regions (P < 0.05). New Delhi MBL (NDM) was the most common MBL (83.3%). ATM-AVI demonstrated potent activity against MBL-positive isolates (MIC ≤8 mg/L: 99.4% isolates inhibited; MIC, 1 mg/L). Consistent activity was also noted across different regions. Potent activity was demonstrated against different NDM variants and MBL-positive isolates co-carrying other carbapenemases (98.1% and 99.7% isolates inhibited at ≤8 mg/L, respectively). About 0.6% MBL-positive isolates (10/1707) had MICs >8 mg/L for ATM-AVI.
CONCLUSION
ATM-AVI demonstrated potent activity against MBL-positive isolates, including NDM variants and MBL-positive isolates co-carrying other carbapenemases, and may represent a good option for treating infections caused by MBL-positive Enterobacterales.
Topics: Aztreonam; beta-Lactamases; Azabicyclo Compounds; Ascomycota; Gammaproteobacteria; Anti-Infective Agents
PubMed: 38154750
DOI: 10.1016/j.jgar.2023.12.027 -
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 -
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