Ontology highlight
ABSTRACT:
PROVIDER: PRJNA949836 | ENA |
REPOSITORIES: ENA
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Project description:Pseudomonas aeruginosa is a leading cause of hospital acquired infections for which the development of new antibiotics is urgently needed. Unlike most enteric bacteria, P. aeruginosa lacks thymidine kinase and thymidine phosphorylase activity, and thus cannot scavenge exogenous thymine. An appealing strategy to selectively target P. aeruginosa while leaving the healthy microbiome largely intact would thus be to disrupt thymidine synthesis while providing exogenous thymine. However, this approach was previously intractable because known antibiotics that perturb thymidine synthesis are largely inactive against P. aeruginosa. Here, we characterize a novel dihydrofolate reductase inhibitor, fluorofolin, that exhibits significant activity against P. aeruginosa in culture and in a mouse thigh infection model. Fluorofolin is active against a wide range of clinical P. aeruginosa isolates resistant to known antibiotics, including critical antibiotic development priorities expressing the beta-lactamases KPC-5 and NDM-1. Importantly, in the presence of thymine supplementation, fluorofolin activity is selective for P. aeruginosa. Resistance to fluorofolin can emerge through overexpression of the efflux pumps MexCD-OprJ and MexEF-OprN. However, these mutants also decrease pathogenesis, in part due to increased export of quorum sensing precursors leading to decreased virulence factor production. Our findings thus demonstrate how understanding species-specific genetic differences and discovery of an antibiotic with a widely conserved target can enable selective targeting of important pathogens while revealing new tradeoffs between resistance and pathogenesis.
2024-02-07 | GSE249862 | GEO
Project description:The objective is to generate a robust and validated predictor profile for chemotherapy response in patients with mCRC using microarray gene expression profiles of primary colorectal cancer tissue. To define a gene signature of response to chemotherapy in metastatic colorectal cancer, samples were obtained from 40 patients from Marques de Valdecilla Hospital who underwent primary surgery. Gene expression was detected and quantified using the Human Whole Genome U133 Plus 2.0 array (Affymetrix), containing 54675 human gene probes. The validation set consisted of 119 samples from Hospital Virgen del Rocio, Seville, Spain; Hospital Virgen de la Victoria, Malaga, Spain; Hospital de la Merced, Osuna, Spain and Hospital MarquM-CM-)s de Valdecilla, Santander, Spain, and included 86 tumor samples (40 coming from the training set and 46 from newly treated CRC patients) and 33 normal tissue samples of CRC patients used as controls. Custom-designed TaqManM-BM-. Low Density Arrays (TLDA) 7900 HT Micro Fluidic Cards including the 161 genes selected for validation were run and analyzed by the ABI PRISMM-BM-. 7900HT Sequence Detection System (SDS 2.2, Applied Biosystems) according to manufacturer's protocol (Applied Biosystems). Expression of target miRNAs was normalized in relation to the expression of GAPDH. Cycle threshold (Ct) values were calculated using the SDS software v.4.2 using automatic baseline settings and a threshold of 0.2. Relative quantification of gene expression was calculated by the 2M-bM-^HM-^RM-NM-^TCt method (Applied Biosystems user bulletin no. 2 (P/N 4303859)). This submission represents the RT-PCR component of the study only
2013-11-20 | E-GEOD-52513 | biostudies-arrayexpress
Project description:The spread of carbapenemase-producing Enterobacterales (CPE) is emerging as a significant clinical concern in tertiary hospitals and in particular, long-term care facilities with deficiencies in infection control. This study aims to evaluate an advanced matrix-assisted laser desorption/ionization mass spectrometry (A-MALDI) method for the identification of carbapenemases and further discrimination of their subtypes in clinical isolates. The A-MALDI method was employed to detect CPE target proteins. Enhancements were made to improve detectability and mass accuracy through the optimization of MALDI-TOF settings and internal mass calibration. A total of 581 clinical isolates were analyzed, including 469 CPE isolates (388 KPC, 51 NDM, 40 OXA, and 2 GES) and 112 carbapenemase-negative isolates. Clinical evaluation of the A-MALDI demonstrated 100% accuracy and precision in identifying all the collected CPE isolates. Additionally, A-MALDI successfully discriminated individual carbapenemase subtypes (KPC-2 or KPC-3/4; OXA-48 or OXA-181 or OXA-232; GES-5 or GES-24) and also differentiated co-producing carbapenemase strains (KPC & NDM; KPC & OXA; KPC & GES; NDM & OXA), attributed to its high mass accuracy and simultaneous detection capability. A-MALDI is considered a valuable diagnostic tool for accurately identifying CPE and carbapenemase’s subtypes in clinical isolates. It may also aid in selecting appropriate antibiotics for each carbapenemase subtype. Ultimately, we expect that the A-MALDI method will contribute to preventing the spread of antibiotic resistance and improving human public health.
2024-11-26 | PXD058284 | Pride
Project description:Antibiotic resistance associated with the expression of the clinically significant carbapenemases, IMP, KPC, and NDM and OXA-48 in Enterobacteriaceae is emerging as a worldwide calamity to health care. In Australia, IMP-producing Enterobacteriaceae is the most prevalent carbapenemase-producing Enterobacteriaceae (CPE). Genomic characteristics of such carbapenemase-producing Enterobacteriaceae (CPE) are well described, but the corresponding proteome is poorly characterised. We have thus developed a method to analyse dynamic changes in the proteome of CPE under antibiotic pressure. Specifically, we have investigated the effect of meropenem at sub-lethal concentrations to develop a better understanding of how antibiotic pressure leads to resistance. Escherichia coli, producing either NDM, IMP or KPC type carbapenemase were included in this study, and their proteomes were analysed in growth conditions with or without meropenem.
2018-07-11 | PXD008019 | Pride
Project description:Detection of NDM variants of Citrobacter werkmanii in Hospital sewage water
| PRJNA353891 | ENA