Beta-Lactamase diversity in the General Hospital Vienna
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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:Bactericidal antibiotics are powerful drugs because they not only inhibit essential bacterial functions, but convert them into toxic processes. Many bacteria are remarkably tolerant against antibiotics, due to inducible damage repair responses. How these responses promote whole population tolerance in important human pathogens is poorly understood. The two-component system VxrAB of the diarrheal pathogen Vibrio cholerae, a model system for tolerance against cell wall damaging (e.g., beta-lactam) antibiotics, is required for high-level beta-lactam tolerance. Here, we report the mechanism of VxrAB-mediated survival. We find that -lactam antibiotics inappropriately induce the Fur-regulated iron starvation response, causing an increase in intracellular free iron and colateral oxidative damage. VxrAB reduces antibiotic-induced toxic influx of Fe by downregulating iron importers and induces cell wall synthesis functions to counteract cell wall damage. Our results highlight the complex responses elicited by antibiotics and suggest that the ability to counteract diverse stresses promotes high-level antibiotic tolerance.
2019-07-30 | GSE135010 | GEO
Project description:Bactericidal antibiotics are powerful drugs because they not only inhibit essential bacterial functions, but convert them into toxic processes. Many bacteria are remarkably tolerant against antibiotics, due to inducible damage repair responses. How these responses promote whole population tolerance in important human pathogens is poorly understood. The two-component system VxrAB of the diarrheal pathogen Vibrio cholerae, a model system for tolerance against cell wall damaging (e.g., beta-lactam) antibiotics, is required for high-level beta-lactam tolerance. Here, we report the mechanism of VxrAB-mediated survival. We find that -lactam antibiotics inappropriately induce the Fur-regulated iron starvation response, causing an increase in intracellular free iron and colateral oxidative damage. VxrAB reduces antibiotic-induced toxic influx of Fe by downregulating iron importers and induces cell wall synthesis functions to counteract cell wall damage. Our results highlight the complex responses elicited by antibiotics and suggest that the ability to counteract diverse stresses promotes high-level antibiotic tolerance.
2019-07-30 | GSE135009 | GEO
Project description:Carbapenem-resistant Acinetobacter baumannii (CRAb) is an urgent public health threat, according to the CDC. This pathogen has few treatment options and causes severe nosocomial infections with >50% fatality rate. Although previous studies have examined the proteome of CRAb, there have been no focused analyses of dynamic changes to β-lactamase expression that may occur due to drug exposure. Here, we present our initial proteomic study of variation in β-lactamase expression that occurs in CRAb with different β-lactam antibiotics. Briefly, drug resistance to Ab (ATCC 19606) was induced by the administration of various classes of β-lactam antibiotics, and the cell-free supernatant was isolated, concentrated, separated by SDS-PAGE, digested with trypsin, and identified by label-free LC-MS-based quantitative proteomics. Thirteen proteins were identified and evaluated using a 1789 sequence database of Ab β-lactamases from UniProt, the majority of which were Class C β-lactamases (≥80%). Importantly, different antibiotics, even those of the same class (e.g. penicillin and amoxicillin), induced non-equivalent responses comprising various isoforms of Class C and D serine-β-lactamases, resulting in unique resistomes. These results open the door to a new approach of analyzing and studying the problem of multi-drug resistance in bacteria that rely strongly on β-lactamase expression.
2023-07-20 | PXD042336 | Pride
Project description:Recurrent epidemics of methicillin-resistant Staphylococcus aureus (MRSA) have illustrated that the effectiveness of antibiotics in clinical application is rapidly fading. A feasible approach is to combine natural products with existing antibiotics to achieve an antibacterial effect. In this molecular docking study, we found that theaflavin (TF) preferentially binds the allosteric site of penicillin-binding protein 2a (PBP2a), inducing the PBP2a active site to open, which is convenient for β-lactam antibiotics to treat MRSA infection, instead of directly exerting antibacterial activity at the active site. Subsequent TMT-labeled proteomics analysis showed that TF treatment did not significantly change the landscape of the Staphylococcus aureus (S. aureus) USA300 proteome.Checkerboard dilution tests and kill curve assays were performed to validate the synergistic effect of TF and ceftiofur, and the fractional inhibitory concentration index (FICI) was 0.1875.Our findings provide a potential therapeutic strategy to combine existing antibiotics with natural products to resolve the prevalent infections of multidrug-resistant pathogens.
2022-11-09 | PXD037668 | Pride
Project description:Stenotrophomonas maltophilia K279a diverges into subpopulations with distinct but reversible phenotypes of small and big colonies when challenged with ampicillin. This observation is consistent with the formation of long cell chains during exponential growth phase and the occurrence of mainly coccoid– or rod-shaped cells in liquid media. Further, scanning electron micrographs of SMK279a revealed that cells formed gigantic outer membrane vesicles in response to β-lactam treatment. RNA-seq analysis of small vs. big colonies unveiled that cells regulate at least seven genes differentially among colony morphotypes. Among those were the blaL1 and blaL2 genes the most strongly regulated ones with an eleven- and six-fold increased transcription, respectively. Further studies with promoter fusions of blaL1 and blaL2 genes implied that expression of both genes is also subject to high levels of phenotypic heterogeneous expression on a single cell level. Additional RNA-seq analysis of this homogenously versus heterogeneously blaL2 expressing cells identified comE homologue as differentially expressed, in which by the expression of extra copies of comE in S. maltophilia K279a reduced the level of those cells that were in a blaL2-ON model to 1% or lower. Together with genome-wide sequence analysis of cells from the different colony morphotypes, the data presented here suggests that phenotypic heterogeneity in S. maltophilia K279a is a result of non-genetic variations within isogenic populations and also polymorphisms in this strain do not influence β-lactamase resistance phenotype.
2015-11-18 | GSE71735 | GEO
Project description:Non-typeable Haemophilus influenzae (NTHi) is a common acute otitis media pathogen, with an incidence that is increased by previous antibiotic treatment. NTHi is also an emerging causative agent of other chronic infections in humans, some linked to morbidity, and all of which impose substantial treatment costs. In this study we explore the possibility that antibiotic exposure may stimulate biofilm formation by NTHi bacteria. We discovered that sub-inhibitory concentrations of beta-lactam antibiotic (i.e., amounts that partially inhibit bacterial growth) stimulated the biofilm-forming ability of NTHi strains, an effect that was strain and antibiotic dependent. When exposed to sub-inhibitory concentrations of beta-lactam antibiotics NTHi strains produced tightly packed biofilms with decreased numbers of culturable bacteria but increased biomass. The ratio of protein per unit weight of biofilm decreased as a result of antibiotic exposure. Antibiotic-stimulated biofilms had altered ultrastructure, and genes involved in glycogen production and transporter function were up regulated in response to antibiotic exposure. Down-regulated genes were linked to multiple metabolic processes but not those involved in stress response. Antibiotic-stimulated biofilm bacteria were more resistant to a lethal dose (10M-BM-5g/mL) of cefuroxime. Our results suggest that beta-lactam antibiotic exposure may act as a signaling molecule that promotes transformation into the biofilm phenotype. Loss of viable bacteria, increase in biofilm biomass and decreased protein production coupled with a concomitant up-regulation of genes involved with glycogen production might result in a biofilm of sessile, metabolically inactive bacteria sustained by stored glycogen. These biofilms may protect surviving bacteria from subsequent antibiotic challenges, and act as a reservoir of viable bacteria once antibiotic exposure has ended. 12 samples
2014-06-04 | E-GEOD-58213 | biostudies-arrayexpress
Project description:We performed RNA-seq experiments to compare the gene expression profiles of cells expressing TEM-1 beta-lactamase with single-codon substitutions in the absence of beta-lactam antibiotics. Mutations with deleterious fitness effects in the absense of antibiotics also caused significant changes in gene expression, primarily in the induction of specific outer envelope stress response pathways and, in some cases, the mild-induction of a few genes in the heat-shock response pathway.
2019-10-28 | GSE137362 | GEO
Project description:Beta-lactam resistant isolates Genome sequencing
| PRJNA543210 | ENA
Project description:Beta-lactam non-susceptible GAS from clinical samples in Guyana
| PRJEB68215 | ENA