Allele-Specific Effects of Mutations in the Rifampin Resistance-Determining Region (RRDR) of RpoB on Physiology and Antibiotic Resistance in Enterococcus faecium
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ABSTRACT:
PROVIDER: PRJNA1292192 | ENA |
REPOSITORIES: ENA
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Project description:Enterococcus faecium is a member of the human gut microbiota that has evolved to be a problematic nosocomial pathogen and a leading cause of bloodstream infections in hospitalized patients. Treatment of E. faecium infections is complicated by antibiotic resistance, making it important to understand resistance mechanisms and their broader consequences in this pathogen. Here we explored the collateral effects of rifampin resistance-associated mutations in the E. faecium RNA polymerase β-subunit (RpoB). Of 14,384 publicly available E. faecium genomes, nearly one-third carried a mutation in the rifampin resistance-determining region (RRDR) of RpoB. In a local population of 710 E. faecium isolates collected from patients at a single medical center, we found significant associations between the presence of RRDR mutations and prior exposure to rifamycin class antibiotics, as well as associations between RRDR mutations and altered daptomycin susceptibility. To investigate the phenotypic impacts of RRDR mutations, we studied four isogenic strains with distinct RRDR mutations (Q473K, G482D, H486Y, S491L) that overlapped with clinical isolate variants. Transcriptomic and phenotypic analyses revealed allele-specific effects on E. faecium gene expression, growth dynamics, antibiotic susceptibility, isopropanol tolerance, and cell wall physiology. One frequently observed mutation, H486Y, caused minimal transcriptional changes and enhanced bacterial fitness. In contrast, the S491L mutation induced extensive transcriptional changes and slowed bacterial growth, but also conferred increased isopropanol tolerance, potentially enhancing bacterial survival in the hospital environment. Overall, our findings highlight the multifaceted impacts of RRDR mutations in shaping E. faecium physiology and antibiotic resistance, two important features of this hospital-associated pathogen.
2025-08-10 | GSE302807 | GEO
Project description: Not available
| S-EPMC12724266 | biostudies-literature
Project description:Rifampin causes drug interactions by altering hepatic drug metabolism. Because microRNAs (miRNAs) have been shown to regulate genes involved in drug metabolism, we determined the effect of rifampin on the expression of hepatic miRNAs. Primary human hepatocytes from seven subjects were treated with rifampin, and the expression of miRNA and cytochrome P450 (P450) mRNAs was measured by TaqMan assays and RNA-seq, respectively. Rifampin induced the expression of 10 clinically important and 13 additional P450 genes and repressed the expression of 9 other P450 genes (P < 0.05). Rifampin induced the expression of 33 miRNAs and repressed the expression of 35 miRNAs (P < 0.05). Several of these changes were highly negatively correlated with the rifampin-induced changes in the expression of their predicted target P450 mRNAs, supporting the possibility of miRNA-induced regulation of P450 mRNA expression. In addition, several other miRNA changes were positively correlated with the changes in P450 mRNA expression, suggesting similar regulatory mechanisms. Despite the interindividual variability in the rifampin effects on miRNA expression, principal components analysis clearly separated the rifampin-treated samples from the controls. In conclusion, rifampin treatment alters miRNA expression patterns in human hepatocytes, and some of the changes were correlated with the rifampin-induced changes in expression of the P450 mRNAs they are predicted to target. Primary human hepatocytes were treated rifampin or vehicle for 24 hours. Rifampin-treated samples are not available for the 30Jul10 patient or the Hep2 patient due to raw data file corruption.
2016-04-06 | E-GEOD-79933 | biostudies-arrayexpress
Project description:Rifampin causes drug interactions by altering hepatic drug metabolism. Because microRNAs (miRNAs) have been shown to regulate genes involved in drug metabolism, we determined the effect of rifampin on the expression of hepatic miRNAs. Primary human hepatocytes from seven subjects were treated with rifampin, and the expression of miRNA and cytochrome P450 (P450) mRNAs was measured by TaqMan assays and RNA-seq, respectively. Rifampin induced the expression of 10 clinically important and 13 additional P450 genes and repressed the expression of 9 other P450 genes (P < 0.05). Rifampin induced the expression of 33 miRNAs and repressed the expression of 35 miRNAs (P < 0.05). Several of these changes were highly negatively correlated with the rifampin-induced changes in the expression of their predicted target P450 mRNAs, supporting the possibility of miRNA-induced regulation of P450 mRNA expression. In addition, several other miRNA changes were positively correlated with the changes in P450 mRNA expression, suggesting similar regulatory mechanisms. Despite the interindividual variability in the rifampin effects on miRNA expression, principal components analysis clearly separated the rifampin-treated samples from the controls. In conclusion, rifampin treatment alters miRNA expression patterns in human hepatocytes, and some of the changes were correlated with the rifampin-induced changes in expression of the P450 mRNAs they are predicted to target.
2016-04-06 | GSE79933 | GEO
Project description:This study investigates the role of the phosphate-specific transport system gene pstA1 in rifampin tolerance in Mycobacterium tuberculosis. We constructed a pstA1 deletion mutant (ΔpstA1) and demonstrated that it exhibits enhanced rifampin susceptibility compared to wild-type H37Rv. To explore the molecular mechanisms underlying this phenotype, we performed RNA-seq transcriptomic analysis comparing wild-type and ΔpstA1 strains grown in standard Middlebrook 7H9 broth under exposure to sub-inhibitory rifampin (7.5 ng/ml, 1/4 MIC) for 30 or 60 minutes. The analysis revealed substantial transcriptional reprogramming in ΔpstA1, providing insights into how loss of PstA1 function leads to increased rifampin susceptibility.
2025-11-27 | GSE310692 | GEO
Project description:Many clinically relevant bacterial pathogens are encapsulated, as exemplified by Salmonella enterica serovar Typhi. S. Typhi, the causative agent of the life-threatening systemic disease enteric fever, expresses Vi as the outermost surface glycan that protects the bacteria from host immune responses. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) S. Typhi strains, as well as Vi variants, are widespread globally. Our WGS analyses indicate that almost all S. Typhi clinical isolates are susceptible to rifamycins and azithromycin. Rifampin, even at sub-MIC levels, eliminates the protective capsule Vi, a process referred to as ‘decapsulation’, thereby enhancing bacterial clearance. Antibiotic-mediated decapsulation of S. Typhi appears specific to rifamycins, since azithromycin does not decapsulate S. Typhi. Rifampin mediated decapsulation occurs at the transcriptional level, where both high AT content and specific RpoB residues play a crucial role. Rifampin also effectively decapsulates Vi variants, which accounts for 1 in 5 S. Typhi isolates at the global level. A mechanistic explanation for rifampin mediated decapsulation of S. Typhi appears to be applicable to other encapsulated pathogens, including S. Paratyphi C.
2025-05-15 | GSE295448 | GEO
Project description:RATIONALE: Studying samples of blood and tissue in the laboratory from patients with cancer and from healthy participants may help doctors learn more about cancer.
PURPOSE: This laboratory study is looking at an assay in determining cancer resistance in patients with metastatic cancer and in healthy participants.
| 2072144 | ecrin-mdr-crc
Project description:Comparing of induced cellular cytokine profile in response to Rifampin-mono resistant and H37Rv Mycobacterium tuberculosis strains
2018-06-11 | GSE115546 | GEO
Project description: Not available
| S-EPMC4844700 | biostudies-literature
Project description:We report the application of next generation sequencing technology for high-throughput profiling of total RNA to determine the expression of all genes expressed in human primary hepatocytes derived from three healthy (drug/tobacco/alcohol free) volunteers in response to anti-tuberculosis antibiotics, including, rifampin, rifabutin and rifapentine through comparison with gene profiles of vehicle (methanol) treated and untreated cells. We determined the response of over 22,000 genes expressed in human primary hepatocytes following rifampin, rifabutin and rifapentine treatment for 72h. We found that several drug metabolizing enzymes, including cytochrome P450 3A4 and drug transporters are differentially expressed in human primary hepatocytes in response to rifamycin antibiotics. We utilized the information generated with differential gene expression study to determine interaction of rifamyicn antibiotics with antiviral, antibacterial, antifungal agents and other drugs used to treat several ailments in tuberculosis patients. This study provides a comprehensive profiles of genes expressed in response to rifamycin antibiotics towards characterization of their drug interactions with the drugs that are combined to treat various viral, bacterial, fungal and other diseases, including cancer.
2020-03-26 | GSE139896 | GEO