Ontology highlight
ABSTRACT:
PROVIDER: PRJNA785334 | ENA |
REPOSITORIES: ENA
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Project description:The antibiotic fosfomycin is widely recognized for treatment of lower urinary tract infections caused by Escherichia coli and lately gained importance as a therapeutic option to combat multidrug resistant bacteria. Still, resistance to fosfomycin frequently develops through mutations reducing its uptake. Whereas the inner membrane transport of fosfomycin has been extensively studied in E. coli, its outer membrane (OM) transport remains insufficiently understood. While evaluating minimal inhibitory concentrations in OM porin-deficient mutants, we observed that the E. coli ΔompCΔompF strain is five times more resistant to fosfomycin than the wild type and the respective single mutants. Continuous monitoring of cell lysis of porin-deficient strains in response to fosfomycin additionally indicated the relevance of LamB. Furthermore, the physiological relevance of OmpF, OmpC and LamB for fosfomycin uptake was confirmed by electrophysiological and transcriptional analysis. This study expands the knowledge of how fosfomycin crosses the OM of E. coli.
2024-01-24 | GSE236554 | GEO
Project description:Staphylococcus aureus is a highly adaptable human pathogen; therefore a constant search for new effective antibiotic compounds is being preformed. Gene expression profiling can be used to determine potential targets and mechanisms of action (MOA) of known or potential drugs. The goal of our study was a development of a focused transcriptome platform to be used for confirming the MOA of new chemical entities which are designed as inhibitors of Mur ligases. A model transcriptional profile was set up for well described inhibitor of MurA ligase, fosfomycin. Moreover, we wanted to identify the pathways and processes primarily affected by this compound. S. aureus ATCC 29213 cells were treated with low concentrations of fosfomycin (1 and 4 µg/ml, respectively) and harvested at 10, 20 and 40 minutes after treatment, respectively. RNA was isolated, transcribed, labeled and hybridized to S. aureus GeneChips, representing approximately 3000 S. aureus genes. Using meta-analysis of our results and the results in the S. aureus microarray database, we have confirmed that fosfomycin induces âcell wall stimulonâ genes and were able to identify genes and pathways specifically modulated by fosfomycin. Time course, different fosfomycin concentration
2010-05-20 | E-GEOD-15394 | biostudies-arrayexpress
Project description:Urinary tract infections (UTIs) are one of the most common bacterial infections in humans, with ~400 million cases across the globe each year. Uropathogenic E. coli (UPEC) is the major cause of UTI and increasingly associated with antibiotic resistance. This scenario has been worsened by the emergence and spread of pandemic UPEC sequence type 131 (ST131), a multidrug-resistant clone associated with extraordinarily high rates of infection. Here, we employed transposon-directed insertion site sequencing in combination with metabolomic profiling to identify genes and biochemical pathways required for growth and survival of the UPEC ST131 reference strain EC958 in human urine (HU). We identified 24 UPEC genes required for growth in HU, which mapped to diverse pathways involving small peptide, amino acid and nucleotide metabolism, the stringent response pathway, and lipopolysaccharide (LPS) biosynthesis. We also discovered a role for UPEC resistance to fluoride during growth in HU, most likely associated with fluoridation of drinking water. Complementary NMR-based metabolomics identified changes in a range of HU metabolites following UPEC growth, the most pronounced being L-lactate, which was utilized as a carbon source via the L-lactate dehydrogenase LldD. Using a mouse UTI model with mixed competitive infection experiments, we demonstrated a role for nucleotide metabolism and the stringent response in UPEC colonization of the mouse bladder. Together, our application of multiple omics technologies combined with different infection-relevant settings has uncovered new factors required for UPEC growth in HU, thus enhancing our understanding of this pivotal step in the UPEC infection pathway.
2024-02-09 | MTBLS9131 | MetaboLights
Project description:Fosfomycin is a bactericidal antibiotic, analogous to phosphoenolpyruvate (PEP) that exerts its activity by inhibiting the activity of MurA. This enzyme catalyzes the first step of peptidoglycan biosynthesis, the transfer of enolpyruvate from PEP to uridine- diphosphate-N-acetylglucosamine. Fosfomycin is increasingly used in the last years, mainly for treating infections caused by Gram-negative multidrug resistant bacteria as Stenotrophomonas maltophilia, an opportunistic pathogen characterized by its low susceptibility to antibiotics of common use. The mechanisms of mutational resistance to fosfomycin in Stenotrophomonas maltophilia were studied in the current work. None of the mechanisms so far described for other organisms, which include the production of fosfomycin inactivating enzymes, target modification, induction of alternative peptidoglycan biosynthesis pathway and the impaired entrance of the antibiotic, are involved in the acquisition of such resistance by this bacterial species. Rather the unique cause of resistance in the studied mutants is the mutational inactivation of different enzymes belonging to the Embden-Meyerhof-Parnas central metabolism pathway. The amount of intracellular fosfomycin accumulation did not change in any of these mutants showing that neither the inactivation nor the transport of the antibiotic were involved. Transcriptomic analysis also showed that the mutants did not present changes in the expression level of putative alternative peptidoglycan biosynthesis pathway genes neither any related enzyme. Finally, the mutants did not present an increased PEP concentration that might compete with fosfomycin for its binding to MurA. Based on these results, we describe a completely novel mechanism of antibiotic resistance based on the remodeling of S. maltophilia metabolism.
2020-05-11 | GSE141276 | GEO
Project description:More than half of women will experience a urinary tract infection (UTI) with uropathogenic Escherichia coli (UPEC) causing ~80% of uncomplicated cases. Iron acquisition systems are essential for uropathogenesis, and UPEC encode functionally redundant iron acquisition systems, underlining their importance. However, a recent UPEC clinical isolate, HM7 lacks this functional redundancy and instead encodes a sole siderophore, enterobactin. To determine if E. coli HM7 possesses unidentified iron acquisition systems, we performed RNA-sequencing under iron-limiting conditions and demonstrated the ferric citrate uptake system (fecABCDE and fecIR) was highly upregulated. Importantly, there are high levels of citrate within urine, some of which is bound to iron, and the fec system is highly enriched in UPEC isolates compared to commensal or fecal strains. Therefore, we hypothesized that HM7 and other similar strains use the fec system to acquire iron in the host. Deletion of both enterobactin biosynthesis and ferric citrate uptake (ΔentB/ΔfecA) abrogates use of ferric citrate as an iron source and fecA provides an advantage in pooled human urine in absence of enterobactin. However, in a UTI mouse model, fecA is a fitness factor independent of enterobactin production, likely due to the action of host Lipocalin-2 chelating ferrienterobactin. These findings indicate that ferric citrate uptake is used as an iron source when siderophore efficacy is limited, such as in the host during UTI. Defining these novel compensatory mechanisms and understanding the nutritional hierarchy of preferred iron sources within the urinary tract are important in the search for new approaches to combat UTI.
2021-11-06 | GSE188170 | GEO
Project description:Staphylococcus aureus is a highly adaptable human pathogen; therefore a constant search for new effective antibiotic compounds is being preformed. Gene expression profiling can be used to determine potential targets and mechanisms of action (MOA) of known or potential drugs. The goal of our study was a development of a focused transcriptome platform to be used for confirming the MOA of new chemical entities which are designed as inhibitors of Mur ligases. A model transcriptional profile was set up for well described inhibitor of MurA ligase, fosfomycin. Moreover, we wanted to identify the pathways and processes primarily affected by this compound. S. aureus ATCC 29213 cells were treated with low concentrations of fosfomycin (1 and 4 µg/ml, respectively) and harvested at 10, 20 and 40 minutes after treatment, respectively. RNA was isolated, transcribed, labeled and hybridized to S. aureus GeneChips, representing approximately 3000 S. aureus genes. Using meta-analysis of our results and the results in the S. aureus microarray database, we have confirmed that fosfomycin induces “cell wall stimulon” genes and were able to identify genes and pathways specifically modulated by fosfomycin.
2009-03-26 | GSE15394 | GEO