Ontology highlight
ABSTRACT:
PROVIDER: PRJNA994912 | ENA |
REPOSITORIES: ENA
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Project description:Clavulanic acid (CLV) is a betalactam (BL) which inhibits betalactamases activity and is frequently administered combined with amoxicillin (AX). Both BLs can be independently involved in allergic reactions. Indeed, selective immediate allergic reactions to CLV have recently been reported in 30% of patients allergic to the AX-CLV combination. Although protein haptenation with β-lactams is considered necessary to activate the immune system, currently there are no straight-forward detection tools for the study of protein haptenation by CLV. The aim of this study was to assess the suitability of two biotinylated analogues of CLV, CLV-B or CLV-TEG-B (containing the later a hydrophilic tetraethylenglycol linker), as probes to study protein haptenation by this β-lactam. Our results show that tagged CLV keeps some of the features of CLV, as the amide binding by which they haptenate proteins and it could constitute a valuable tool to identify protein targets for haptenation by CLV with high sensitivity to get insights into the activation of the immune system by CLV as well as mechanisms involved in allergy to β-lactams.
2021-09-09 | PXD021675 | Pride
Project description:Mycobacterium abscessus (Mab) causes serious infections that often require over 18 months of antibiotic combination therapy. With β lactam antibiotics being safe, double β-lactam and β-lactam/β-lactamase inhibitor combinations are of interest for improving treatment of Mab infections and minimizing toxicity. However, a mechanistic approach for building these combinations is lacking since little is known about which penicillin-binding protein (PBP) target receptors are inactivated by different β-lactams in Mab. This project aimed to identify PBPs in Mab and study the binding affinities of each of these PBPs with β-lactam antibiotics. These first PBP occupancy patterns in Mab provide a mechanistic foundation for selecting and optimizing safe and effective combination therapies with β-lactams.
2020-11-24 | PXD022644 | Pride
Project description:Bovine Escherichia coli resistant to beta-lactams
| PRJNA566319 | ENA
Project description:Monosomy 7 or deletion of 7q (del(7q)) frequently arise in inherited and acquired bone marrow failure, and are associated with progression to high grade Myelodysplastic Syndrome (MDS) and acute leukemia. Current non-transplant approaches to treat marrow failure may be complicated by potential stimulation of clonal outgrowth. To study the biological consequences of del(7q) within the context of a failing marrow, we utilized induced pluripotent stem cells (iPSCs) derived from patients with Shwachman Diamond Syndrome (SDS) and genomically engineered a deletion of (7q). Deletion of 7q failed to confer a relative fitness advantage in either pluripotent SDS iPSC or in iPSC-derived SDS CD34+ cells. The TGF-beta pathway was the top differentially regulated pathway in transcriptome analysis with the TGF pathway found activated in SDS-iPSCs, compared to SDS-del(7q) iPSCs. Increased phosphorylation of SMAD2 in SDS-iPSCs was reduced following del(7q) and increased upon restoration of 7q diploidy, in support of an effect of 7q dosage on the activation status of the TGF-beta pathway in SDS. Inhibition of the TGF-beta pathway rescued hematopoiesis in SDS-iPSCs and in primary bone marrow cells from SDS patients without improving hematopoiesis of the SDS-del(7q) cells. Together, these results utilizing an iPSC model of MDS in BMF identified a targetable vulnerability for potential therapeutic strategies to ameliorate bone marrow failure without promoting outgrowth of the del7q clone.
2019-07-26 | GSE118377 | GEO
Project description:Monosomy 7 or deletion of 7q (del(7q)) frequently arise in inherited and acquired bone marrow failure, and are associated with progression to high grade Myelodysplastic Syndrome (MDS) and acute leukemia. Current non-transplant approaches to treat marrow failure may be complicated by potential stimulation of clonal outgrowth. To study the biological consequences of del(7q) within the context of a failing marrow, we utilized induced pluripotent stem cells (iPSCs) derived from patients with Shwachman Diamond Syndrome (SDS) and genomically engineered a deletion of (7q). Deletion of 7q failed to confer a relative fitness advantage in either pluripotent SDS iPSC or in iPSC-derived SDS CD34+ cells. The TGF-beta pathway was the top differentially regulated pathway in transcriptome analysis with the TGF pathway found activated in SDS-iPSCs, compared to SDS-del(7q) iPSCs. Increased phosphorylation of SMAD2 in SDS-iPSCs was reduced following del(7q) and increased upon restoration of 7q diploidy, in support of an effect of 7q dosage on the activation status of the TGF-beta pathway in SDS. Inhibition of the TGF-beta pathway rescued hematopoiesis in SDS-iPSCs and in primary bone marrow cells from SDS patients without improving hematopoiesis of the SDS-del(7q) cells. Together, these results utilizing an iPSC model of MDS in BMF identified a targetable vulnerability for potential therapeutic strategies to ameliorate bone marrow failure without promoting outgrowth of the del7q clone.
2019-07-26 | GSE118372 | GEO
Project description:Clavulanic acid (CLV) and amoxicillin, frequently administered in combination, can be independently involved in allergic reactions. Protein haptenation with β-lactams is considered necessary to activate the immune system. The aim of this study was to assess the suitability of biotinylated analogues of CLV as probes to study protein haptenation by this β-lactam. Two synthetic approaches afforded the labelling of CLV through esterification of its carboxylic group with a biotin moiety, via either direct binding (CLV-B) or tetraethylenglycol linker (CLV-TEG-B). The second analogue offered advantages as solubility in aqueous solution and potential lower steric hindrance for both intended interactions, with the protein and with avidin. NMR reactivity studies showed that both CLV and CLV-TEG-B reacts through β-lactam ring opening by aliphatic amino nitrogen, however with different stability of resulting conjugates. Unlike CLV conjugates, that promoted the decomposition of clavulanate fragment, the conjugates obtained with the CLV-TEG-B remained linked, as a whole structure including biotin, to nucleophile and showed a better stability. This was a desired key feature to allow CLV-TEG-B conjugated protein detection at great sensitivity. We have used biotin detection and mass spectrometry (MS) to detect the haptenation of human serum albumin (HSA) and human serum proteins. MS of conjugates showed that HSA could be modified by CLV-TEG-B. Remarkably, HSA preincubation with CLV excess only reduced moderately the incorporation of CLV-TEG-B, which could be attributed to different protein interferences. The CLV-TEG-B fragment with opened β-lactam was detected bound to the 404-430HSA peptide of the treated protein. Incubation of human serum with CLV-TEG-B resulted in the haptenation of several proteins that were identified by 2D-electrophoresis and peptide mass fingerprinting as HSA, haptoglobin, and heavy and light chains of immunoglobulins. Taken together, our results show that tagged-CLV keeps some of the CLV features. Moreover, although we observe a different behaviour in the conjugate stability and in the site of protein modification, the similar reactivity indicates that it could constitute a valuable tool to identify protein targets for haptenation by CLV with high sensitivity to get insights into the activation of the immune system by CLV and mechanisms involved in β-lactams allergy.
2021-09-09 | PXD021727 | Pride
Project description:Background: Enterobacter cloacae complex (ECC) is a common opportunistic pathogen and is responsible for causing various infections in humans. Owing to its inducible chromosomal AmpC β-lactamase (AmpC), ECC is inherently resistant to the 1st- and 2nd- generation cephalosporins. However, whether β-lactams antibiotics enhance ECC resistance remains unclear. Results: In this study, we found that subinhibitory concentrations (SICs) of cefazolin (CFZ) and imipenem (IMP) can advance the expression of AmpC and enhance its resistance towards β-lactams through NagZ in Enterobacter cloacae (EC). Further, AmpC manifested a substantial upregulation in EC in response to SICs of CFZ and IMP. In nagZ knockout EC (ΔnagZ), the resistance to β-lactam antibiotics was rather weakened and the effect of CFZ and IMP on AmpC induction was completely abrogated. NagZ ectopic expression can rescue the induction effects of CFZ and IMP on AmpC and increase ΔnagZ resistance. More importantly, CFZ and IMP have the potential to induce the expression of AmpR's target genes in a NagZ-dependent manner. Conclusions: Our findings suggest that NagZ is a critical determinant for CFZ and IMP to promote AmpC expression and resistance and that CFZ and IMP should be used with caution since they may aggravate ECC resistance. At the same time, this study further improves our understanding of resistance mechanisms in ECC.
2022-07-01 | GSE207144 | GEO
Project description:Acinetobacter baumannii causes high mortality in ventilator-associated pneumonia patients and antibiotic treatment is compromised in multi-drug resistant strains resistant to beta-lactams, carbapenems, cephalosporins, polymyxins and tetracyclines. Among COVID-19 patients receiving ventilator support, multi-drug resistant A. baumannii secondary infection is associated with a two-fold increase in mortality. Here we investigated the use of the 8-hydroxyquinoline ionophore PBT2 to break resistance of A. baumannii to tetracycline class antibiotics.
2021-12-17 | GSE175535 | GEO
Project description:Acinetobacter schindleri Occurrence of antimicrobial resistance with focus on β-lactams resistance
| PRJNA342934 | ENA