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ABSTRACT:
PROVIDER: PRJNA1017663 | ENA |
REPOSITORIES: ENA
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Project description:In bacteria the defence system to counter oxidative stress is orchestrated by three transcriptional factors – SoxS, SoxR and OxyR. Although the transcriptional regulon of these factors are known in many bacteria, similar data is not available for K. pneumoniae. To address this data gap, oxidative stress was induced in K. pneumoniae MGH 78578 using paraquat and the corresponding regulon was identified using RNA-seq. Since soxS was significantly induced , a soxS mutant was constructed to decipher this regulon in K. pneumoniae MGH75878. The ‘oxidative SoxS regulon’, comprising common genes differentially regulated genes in oxidative and soxS regulon was identified from both regulons – characterised a stringent group of genes which were regulated by SoxS during oxidative stress. Efflux pump encoding genes like acrAB-tolC, acrE along with marRABwere identified in the oxidative SoxS regulon. The phenotypic effect of the observed efflux pump regulation was confirmed in the soxS mutant that exhibited an 2 fold reduction in the minimum bactericidal concentration (MBC) against tetracycline compared to that of the isogenic wild type. Impaired efflux activity, allowing tetracycline to be accumulated in the cytoplasm to bactericidal levels, was further confirmed using tetraphenylphosphonium (TPP+) ion accumulation assay. The susceptibility of the soxS mutant against tetracycline was also apparent in vivo, in the zebrafish embryo model. We conclude that the soxS gene could be considered as a genetic target against which an inhibitor could be developed and be used in combinatorial therapy with tetracycline to combat infections associated with multi-drug resistant K. pneumoniae.
2021-05-26 | GSE146844 | GEO
Project description:To compare the expression profile of B. cenocepacia mutants impaired in RND efflux pump encoding genes
2011-04-23 | E-MEXP-2999 | biostudies-arrayexpress
Project description:To compare the expression profile of B. cenocepacia mutants impaired in RND efflux pump encoding genes
2011-04-23 | E-MEXP-2997 | biostudies-arrayexpress
Project description:Efflux pumps are a significant challenge for the development of new antibacterial agents. Overcoming efflux requires an in-depth understanding of efflux pump functions, substrate specificities, and the development of inhibitors. However, the complexities of drug efflux networks have limited such studies. To address these challenges, we report the generation of Efflux KnockOut-35 (EKO-35), a highly susceptible Escherichia coli strain lacking 35 efflux pumps. We demonstrate the utility of this strain by constructing an efflux platform consisting of strains individually expressing genes encoding efflux pumps forming tripartite complexes with the outer membrane channel TolC. This platform was profiled against a curated diverse compound collection, which enabled us to define physicochemical properties that contribute to transport. We also show the E. coli drug efflux network is conditionally essential for growth, and that the platform can be used to investigate efflux pump inhibitor specificities and also efflux pump interplay. We believe EKO-35 and the efflux platform will have widespread application for the study of drug efflux.
2022-08-31 | PXD033975 | Pride
Project description:The number and overlapping substrate repertoire of multidrug efflux pumps in the E. coli genome suggest a physiological role apart from multidrug resistance. This role was investigated using transcriptomic analyses of cDNAs labeled from E. coli AG102 mRNA (hyper drug resistant, marR1) and its isogenic major efflux pump mutants. Keywords: Mutation Analysis
2008-03-11 | GSE10757 | GEO
Project description:Target (MexB) and efflux based mechanisms decreasing the effectiveness of the efflux pump inhibitor D13-9001 in P. aeruginosa PAO1: uncovering a new role for MexMN-OprM in efflux of β-lactams and a novel regulatory circuit (MmnRS) controlling MexMN expression Efflux pumps contribute to antibiotic resistance in Gram-negative pathogens. Correspondingly, efflux pump inhibitors (EPIs) may reverse this resistance. D13-9001 specifically inhibits MexAB-OprM in P. aeruginosa. Mutants with decreased susceptibility to MexAB-OprM inhibition by D13-9001 were identified and these fell into two categories; those having alterations in the target MexB (F628L and ΔV177) and those with mutations in PA1438 (L172P substitution) which encoded a putative sensor kinase of unknown function. The alterations in MexB were consistent with reported structural studies of D13-9001 interaction with MexB. The PA1438L172P alteration mediated a >150-fold upregulation of MexMN pump gene expression and >50-fold upregulation of PA1438 and the neighboring response regulator gene PA1437. We propose that these be renamed as mmnR/mmnS for MexMN Regulator and Sensor. MexMN was shown to partner with the outer membrane channel protein OprM and to pump several β-lactams, monobactams and tazobactam. Upregulated MexMN functionally replaced MexAB-OprM to efflux these compounds but was insusceptible to inhibition by D13-9001. MmnSL172P also mediated a decrease in susceptibility to imipenem / biapenem that was independent of MexMN-OprM. Expression of oprD, encoding the uptake channel for these compounds was downregulated, suggesting that this channel is also part of the MmnSR regulon. RNA-seq of cells encoding MmnSL172P revealed among other things an interrelationships between regulation of mexMN and genes involved in heavy metal resistance.
2018-12-07 | GSE123403 | GEO
Project description:Clofazimine exposure in vitro selects efflux pump mutants and bedaquiline resistance
| PRJNA494324 | ENA
Project description:The acquisition of multi-drug resistance (MDR) determinants jeopardizes treatment of bacterial infections with antibiotics. The tripartite efflux pump AcrAB-NodT confers adaptive MDR in the non-pathogenic α-proteobacterium Caulobacter crescentus via transcriptional induction by first-generation quinolone antibiotics. We discovered that overexpression of AcrAB-NodT by mutation or exogenous inducers confers resistance to cephalosporin and penicillin (β-lactam) antibiotics. Combining two-step mutagenesis-sequencing (Mut-Seq) and cephalosporin-resistant point mutants, we dissected how TipR targets a common operator of divergent tipR and acrAB-nodT promoter in adaptive and/or potentiated AcrAB-NodT-directed efflux. Chemical screening identified compounds that either interfere with DNA-binding by TipR or induce its ClpXP-dependent proteolytic turnover. We found that long-term induction of AcrAB-NodT disfigures the envelope and that homeostatic control by TipR includes co-induction of the DnaJ-like co-chaperone DjlA, to boost pump assembly and/or capacity in anticipation of envelope stress. Thus, the adaptive MDR regulatory circuitry reconciles drug efflux with co-chaperone function for trans-envelope assemblies and maintenance.
2023-11-09 | GSE225487 | GEO