Mutational resistance to novel cephalosporin-β-lactamase inhibitor combinations
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB44132 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR5693884_1.fastq.gz | Fastqsanger.gz | |||
| ERR5693884_2.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Emergence of resistance to novel cephalosporin-β-lactamase inhibitor combinations through the modification of the Pseudomonas aeruginosa MexCD-OprJ efflux pump
| PRJEB44132 | 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 | GSE238117 | GEO
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 | GSE225488 | GEO
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
Project description:Acremonium chrysogenum is the industrial producer of cephalosporin C. We isolated a mutant (AC554) from a T-DNA inserted library of A. chrysogenum. AC554 exhibited reduced conidiation and lack of cephalosporin C production. In consistent, the transcription of cephalosporin biosynthetic genes pcbC and cefEF was obviously decreased in AC554. TAIL-PCR and sequence analysis indicated that a T-DNA was inserted in the upstream of an open reading frame (ORF) which was designated AcmybA. Sequence analysis indicated that AcmybA encodes a novel Myb domain containing transcriptional factor. Observation of red fluorescence protein (RFP) tagged AcMybA showed that AcMybA is naturally located in the nuclear of A. chrysogenum. Transcription analysis demonstrated that AcmybA was overexpressed in AC554. In contrast with AC554, the AcmybA deleted mutant (DAcmybA) overproduced conidia in LPE medium and increased cephalosporin production during fermentation. To determine the genes under the influence of AcmybA, we sequenced and compared the transcriptome of DAcmybA, AC554 and the wild-type strain at different developmental stages. Results confirmed the repression of AcMybA on the key conidiation regulatory gene AcbrlA and the cephalosporin biosynthetic genes. Among the targets of AcMybA, 10 putative regulatory genes were selected and overexpressed in A. chrysogenum. Taken together, our results indicate that AcMybA negatively regulates conidiation and cephalosporin production in A. chrysogenum.
2017-11-28 | GSE107388 | GEO
Project description:Cephaloridine (CER) is a classical beta-lactam antibiotic that has long served as a model drug for the study of cephalosporin antibiotic-induced acute tubular necrosis. In the present study, we analyzed gene expression profiles in the kidney of rats given subtoxic and toxic doses of CER in order to identify gene expression alterations closely associated with CER-induced nephrotoxicity. Male Fisher 344 rats were intravenously injected with three different doses (150, 300, and 600 mg/kg) of CER, and sacrificed after 24 h. Only the high dose (600 mg/kg) caused mild proximal tubular necrosis and a slight renal dysfunction. Microarray analysis identified hundreds of genes differentially expressed in the renal cortex following the exposure to CER, which could be classified into two main groups that were deregulated in dose-dependent and high dose-specific manners. The genes upregulated dose-dependently mainly included those involved in detoxification and antioxidant defense, which was considered to be associated with CER-induced oxidative stress. In contrast, the genes showing high dose-specific (lesion-specific) induction included a number of genes related to cell proliferation, which appeared to reflect a compensatory response to CER injury. We also found a subset of G2/M phase genes that exhibited hormesis-like (U-Shape) biphasic dose response; namely, downregulation only at the low and/or middle (subtoxic) doses. Furthermore, we could predict potential transcription regulators responsible for the observed gene expression alterations, such as Nrf2 and E2F family. Among the candidate gene biomarkers, kidney injury molecule 1 was markedly upregulated at the mildly toxic dose, suggesting that this gene can be used as an early and sensitive indicator for cephalosporin nephrotoxicity. In conclusion, our transcriptomic data revealed several characteristic expression patterns of genes associated with specific cellular processes, including oxidative stress response and proliferative response, upon exposure to CER, which may enhance our understandings of molecular mechanisms behind cephalosporin antibiotic-induced nephrotoxicity. Keywords: compound treatment, dose response In the present study, we acquired gene expression profiles in the kidney of rats given subtoxic and toxic doses of cephaloridine (CER) using whole-genome oligonucleotide microarrays. Male rats were injected with vehicle alone and three different doses (150, 300, and 600 mg/kg) of CER, and sacrificed after 24 h. Each dose group contained 3 animals.
2010-05-26 | E-GEOD-10034 | biostudies-arrayexpress
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:Cephaloridine (CER) is a classical beta-lactam antibiotic that has long served as a model drug for the study of cephalosporin antibiotic-induced acute tubular necrosis. In the present study, we analyzed gene expression profiles in the kidney of rats given subtoxic and toxic doses of CER in order to identify gene expression alterations closely associated with CER-induced nephrotoxicity. Male Fisher 344 rats were intravenously injected with three different doses (150, 300, and 600 mg/kg) of CER, and sacrificed after 24 h. Only the high dose (600 mg/kg) caused mild proximal tubular necrosis and a slight renal dysfunction. Microarray analysis identified hundreds of genes differentially expressed in the renal cortex following the exposure to CER, which could be classified into two main groups that were deregulated in dose-dependent and high dose-specific manners. The genes upregulated dose-dependently mainly included those involved in detoxification and antioxidant defense, which was considered to be associated with CER-induced oxidative stress. In contrast, the genes showing high dose-specific (lesion-specific) induction included a number of genes related to cell proliferation, which appeared to reflect a compensatory response to CER injury. We also found a subset of G2/M phase genes that exhibited hormesis-like (U-Shape) biphasic dose response; namely, downregulation only at the low and/or middle (subtoxic) doses. Furthermore, we could predict potential transcription regulators responsible for the observed gene expression alterations, such as Nrf2 and E2F family. Among the candidate gene biomarkers, kidney injury molecule 1 was markedly upregulated at the mildly toxic dose, suggesting that this gene can be used as an early and sensitive indicator for cephalosporin nephrotoxicity. In conclusion, our transcriptomic data revealed several characteristic expression patterns of genes associated with specific cellular processes, including oxidative stress response and proliferative response, upon exposure to CER, which may enhance our understandings of molecular mechanisms behind cephalosporin antibiotic-induced nephrotoxicity. Keywords: compound treatment, dose response
2008-06-23 | GSE10034 | GEO
Project description:Hypermutation due to DNA mismatch repair (MMR) deficiencies can accelerate the development of antibiotic resistance in Pseudomonas aeruginosa. Whether hypermutators generate resistance through predominantly similar molecular mechanisms to wild-type (WT) strains is not fully understood. Here, we show that MMR-deficient P. aeruginosa can evolve resistance to important broad-spectrum cephalosporin/beta-lactamase inhibitor combination antibiotics through novel mechanisms not commonly observed in WT lineages. Using whole-genome sequencing (WGS) and transcriptional profiling of isolates that underwent in vitro adaptation to ceftazidime/avibactam (CZA), we characterized the detailed sequence of mutational and transcriptional changes underlying the development of resistance. Surprisingly, MMR-deficient lineages rapidly developed high-level resistance (>256 μg/mL) largely without corresponding fixed mutations or transcriptional changes in well-established resistance genes. Further investigation revealed that these isolates had paradoxically generated an early inactivating mutation in the mexB gene of the MexAB-OprM efflux pump, a primary mediator of CZA resistance in P. aeruginosa, potentially driving an evolutionary search for alternative resistance mechanisms. In addition to alterations in a number of genes not known to be associated with resistance, 2 mutations were observed in the operon encoding the RND efflux pump MexVW. These mutations resulted in a 4- to 6-fold increase in resistance to ceftazidime, CZA, cefepime, and ceftolozane-tazobactam when engineered into a WT strain, demonstrating a potentially important and previously unappreciated mechanism of resistance to these antibiotics in P. aeruginosa. Our results suggest that MMR-deficient isolates may rapidly evolve novel resistance mechanisms, sometimes with complex dynamics that reflect gene inactivation that occurs with hypermutation. The apparent ease with which hypermutators may switch to alternative resistance mechanisms for which antibiotics have not been developed may carry important clinical implications.
| S-EPMC9718400 | biostudies-literature