Search for a Shared Genetic or Biochemical Basis for Biofilm Tolerance to Antibiotics across Bacterial Species
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ABSTRACT:
ORGANISM(S): Acinetobacter baumannii AB5075 Pseudomonas aeruginosa Staphylococcus aureus
PROVIDER: GSE186080 | GEO | 2021/10/18
REPOSITORIES: GEO
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Project description:Search for a Shared Genetic or Biochemical Basis for Biofilm Tolerance to Antibiotics across Bacterial Species
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Project description:Microbial biofilms are a leading cause of chronic infections in humans and persistent biofouling in industries due to extremely high-level tolerance of biofilm cells to antimicrobial agents. Eradicating mature biofilms is especially challenging because of the protection of the extracellular matrix and slow growth of biofilm cells. Recently, we reported that established biofilms can be effectively removed (e.g. 99.9% dispersion of 48?h Pseudomonas aeruginosa PAO1 biofilms) by shape memory polymer-based dynamic changes in surface topography. Here, we demonstrate that such biofilm dispersion also sensitizes biofilm cells to conventional antibiotics. For example, shape recovery in the presence of 50?µg/mL tobramycin reduced biofilm cell counts by more than 3 logs (2,479-fold) compared to the static flat control. The observed effects were attributed to the disruption of biofilm structure and increase in cellular activities as evidenced by an 11.8-fold increase in intracellular level of adenosine triphosphate (ATP), and 4.1-fold increase in expression of the rrnB gene in detached cells. These results can help guide the design of new control methods to better combat biofilm associated antibiotic-resistant infections. STATEMENT OF SIGNIFICANCE: Microbial infections are challenging due to high-level antibiotic resistance of biofilm cells. The protection of an extracellular matrix and slow growth of biofilm cells render conventional antibiotics ineffective. Thus, it is important to develop new technologies that can remove mature biofilms and sensitize biofilm cells to antibiotics. Recently, we demonstrated that dynamic change in surface topography can remove 48?h Pseudomonas aeruginosa PAO1 biofilms by 99.9%. In this study, we investigated how shape recovery triggered dispersion affect the physiology of biofilm cells and associated antibiotic susceptibility. These results are helpful for understanding biofilm dispersion and developing more effective control methods.
| S-EPMC6231961 | biostudies-literature
Project description:Application of a genome-wide linkage method to identify genotype-phenotype relationships between distantly related strains of E. coli. Each hybridization compares transposon footprinting results from a linkage library under a selective condition with those under a nonselective condition. For each of three conditions, we compare transposon footprinting for a library selected under that condition with those under a reference condition (glucose minimal media). Each experiment was performed in duplicate.
2013-11-30 | E-GEOD-45421 | biostudies-arrayexpress
Project description:ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.
| S-EPMC8672363 | biostudies-literature
Project description:Application of a genome-wide linkage method to identify genotype-phenotype relationships between distantly related strains of E. coli. Each hybridization compares transposon footprinting results from a linkage library under a selective condition with those under a nonselective condition.
2013-11-30 | GSE45421 | GEO
Project description:Although molecular genetic approaches have greatly increased our understanding of the evolution and spread of antibiotic resistance genes, there are fewer studies on the dynamics of antibiotic - bacterial (A-B) interactions, especially with respect to stereochemistry. Addressing this knowledge gap requires an interdisciplinary synthesis, and the development of sensitive and selective analytical tools. Here we describe SAM (stereoselective antimicrobial metabolism) workflow, a novel interdisciplinary approach for assessing bacterial resistance mechanisms in the context of A-B interactions that utilise a combination of whole genome sequencing and mass spectrometry. Chloramphenicol was used to provide proof-of-concept to demonstrate the importance of stereoselective metabolism by resistant environmental bacteria. Our data shows that chloramphenicol can be stereoselectively transformed via microbial metabolism with R,R-(-)-CAP being subject to extensive metabolic transformation by an environmental bacterial strain. In contrast S,S-(+)-CAP is not metabolised by this bacterial strain, possibly due to the lack of previous exposure to this isomer in the absence of historical selective pressure to evolve metabolic capacity.
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Project description:Aneuploidy, in which cells carry an abnormal chromosome count, is detrimental during development yet common in human cancers; why cells differ in tolerance remains unclear. We mapped the genetic basis of aneuploidy tolerance in wild Saccharomyces cerevisiae versus the sensitive lab strain to Ssd1, an RNA-binding protein involved in translation whose loss recapitulates aneuploidy signatures in laboratory yeast. We find Ssd1 localizes to mitochondria, influences localization of nuclear-encoded mitochondrial mRNAs and/or abundance of the encoded proteins, influences mitochondrial function, and minimizes protein aggregates upon chromosome amplification. Recapitulating ssd1D defects with combinatorial drug treatment selectively targets wild-type aneuploids in multiple strains, suggesting therapeutic approaches. Our work adds to elegant studies done in the sensitized laboratory strain to present a mechanistic understanding of aneuploidy tolerance in eukaryotes.
2020-01-08 | GSE132425 | GEO
Project description:Fanconi anaemia (FA) is a cancer predisposition syndrome characterized by cellular sensitivity to DNA interstrand crosslinkers. The molecular defect in FA is an impaired DNA repair pathway. The critical event in activating this pathway is monoubiquitination of FANCD2. In vivo, a multisubunit FA core complex catalyzes this step, but its mechanism is unclear. Here, we report purification of a native avian FA core complex and biochemical reconstitution of FANCD2 monoubiquitination. This demonstrates that the catalytic FANCL E3 ligase subunit must be embedded within the complex for maximal activity and site specificity. We genetically and biochemically define a minimal subcomplex comprising just three proteins (FANCB, FANCL, and FAAP100) that functions as the monoubiquitination module. Residual FANCD2 monoubiquitination activity is retained in cells defective for other FA core complex subunits. This work describes the in vitro reconstitution and characterization of this multisubunit monoubiquitin E3 ligase, providing key insight into the conserved FA DNA repair pathway.
| S-EPMC4051986 | biostudies-literature
Project description:BackgroundCyanobacteria constitute a serious threat to freshwater ecosystems by producing toxic secondary metabolites, e.g. microcystins. These microcystins have been shown to harm livestock, pets and humans and to affect ecosystem service and functioning. Cyanobacterial blooms are increasing worldwide in intensity and frequency due to eutrophication and global warming. However, Daphnia, the main grazer of planktonic algae and cyanobacteria, has been shown to be able to suppress bloom-forming cyanobacteria and to adapt to cyanobacteria that produce microcystins. Since Daphnia's genome was published only recently, it is now possible to elucidate the underlying molecular mechanisms of microcystin tolerance of Daphnia.ResultsDaphnia magna was fed with either a cyanobacterial strain that produces microcystins or its genetically engineered microcystin knock-out mutant. Thus, it was possible to distinguish between effects due to the ingestion of cyanobacteria and effects caused specifically by microcystins. By using RNAseq the differentially expressed genes between the different treatments were analyzed and affected KOG-categories were calculated. Here we show that the expression of transporter genes in Daphnia was regulated as a specific response to microcystins. Subsequent qPCR and dietary supplementation with pure microcystin confirmed that the regulation of transporter gene expression was correlated with the tolerance of several Daphnia clones.ConclusionsHere, we were able to identify new candidate genes that specifically respond to microcystins by separating cyanobacterial effects from microcystin effects. The involvement of these candidate genes in tolerance to microcystins was validated by correlating the difference in transporter gene expression with clonal tolerance. Thus, the prevention of microcystin uptake most probably constitutes a key mechanism in the development of tolerance and adaptation of Daphnia. With the availability of clear candidate genes, future investigations examining the process of local adaptation of Daphnia populations to microcystins are now possible.
| S-EPMC4168211 | biostudies-literature
Project description:Biofilm-forming microorganisms switch between two forms: free-living planktonic and sessile multicellular. Sessile communities of yeast biofilms in liquid medium provide a primitive example of multicellularity and are clinically important because biofilms tend to have other growth characteristics than free-living cells. We investigated the genetic basis for yeast, Saccharomyces cerevisiae, biofilm on solid surfaces in liquid medium by screening a comprehensive deletion mutant collection in the ?1278b background and found 71 genes that were essential for biofilm development. Quantitative northern blots further revealed that AIM1, ASG1, AVT1, DRN1, ELP4, FLO8, FMP10, HMT1, KAR5, MIT1, MRPL32, MSS11, NCP1, NPR1, PEP5, PEX25, RIM8, RIM101, RGT1, SNF8, SPC2, STB6, STP22, TEC1, VID24, VPS20, VTC3, YBL029W, YBL029C-A, YFL054C, YGR161W-C, YIL014C-A, YIR024C, YKL151C, YNL200C, YOR034C-A, and YOR223W controlled biofilm through FLO11 induction. Almost all deletion mutants that were unable to form biofilms in liquid medium also lost the ability to form surface-spreading biofilm colonies (mats) on agar and 69% also lost the ability to grow invasively. The protein kinase A isoform Tpk3p functioned specifically in biofilm and mat formation. In a tpk3 mutant, transcription of FLO11 was induced three-fold compared with wild-type, but biofilm development and cell-cell adhesion was absent, suggesting that Tpk3p regulates FLO11 positive posttranscriptionally and negative transcriptionally.The study provides a resource of biofilm-influencing genes for additional research on biofilm development and suggests that the regulation of FLO11 is more complex than previously anticipated.
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