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PROVIDER: PRJNA1268192 | ENA |
REPOSITORIES: ENA
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Project description:Daptomycin represents a reserve antibiotic effective against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Daptomycin resistance (Dap-R) and clinical treatment failure has been associated with adaptive chromosomal mutations, but so far not with acquisition of specific resistance genes. We previously isolated Staphylococcus/Mammaliicoccus sciuri strain TS92, which displays high-level Dap-R but lacks reported adaptive mutations. To identify the underlying resistance mechanism, we performed transcription profiling upon daptomycin exposure of TS92, with subsequent subcloning and mutational analysis of candidate genes. In TS92, Dap-R is mediated by a novel two-gene operon (named drcAB), controlled by an adjacent two-component regulatory system (drcRS). Heterologous drc expression demonstrated drcAB to be required and sufficient to mediate Dap-R in S. aureus (including clinically relevant MRSA) and Bacillus subtilis via inactivation of the antibiotic. The drc genes and proteins show homologies to membrane-associated antimicrobial peptide (AMP) transporters of Gram-positive bacteria but are distinct from currently known systems. In TS92, drc is flanked by insertion sequences (IS) and integrated near a staphylococcal cassette chromosome (SCC) element, suggesting mobility and acquisition of the locus from another species. Consistent with this hypothesis, IS-flanked drc was identified in various bacterial backgrounds in database searches. Here we report for the first time a horizontally acquired Dap-R mechanism that appears to circulate among Gram-positive bacteria, including staphylococci and enterococci. Increasing clinical daptomycin usage increases the likelihood that drc may enter S. aureus and other pathogens, which calls for vigilant monitoring of drc spread and prudent use of the antibiotic.
2025-04-29 | GSE255509 | GEO
Project description:Corynebacterium Striatum endocarditis after renal transplantation confirmed by metagenomic next-generation sequencing: case report
| PRJNA863088 | ENA
Project description:Acquisition of daptomycin resistance results in decreased virulence
| PRJEB72842 | ENA
Project description:Phylogenetic analyses of antimicrobial resistant Corynebacterium striatum strains
| PRJNA1058672 | ENA
Project description:Daptomycin is a lipopeptide antibiotic that has recently been approved for treatment of Gram-positive bacterial infections. The mode of action of daptomycin is not yet entirely clear. To further understand the mechanism transcriptomic analysis of changes in gene expression in daptomycin-treated Staphylococcus aureus was carried out. The expression profile indicated that cell wall stress stimulon member genes (B. J. Wilkinson, A. Muthaiyan, and R. K. Jayaswal. 2005. Curr. Med. Chem. Anti-Infective Agents 4: 259-276) were significantly induced by daptomycin, and by the cell wall-active antibiotics vancomycin and oxacillin. Comparison of the daptomycin response of a two-component cell wall stress stimulon regulator VraSR mutant, S. aureus KVR, to its parent N315 showed diminished expression of the cell wall stress stimulon in the mutant. Daptomycin has been proposed to cause membrane depolarization, and the transcriptional responses to carbonyl cyanide m-chlorophenylhydrazone (CCCP) and nisin were determined. Transcriptional profiles of the responses to these antimicrobial agents showed significantly different patterns compared to those of the cell wall-active antibiotics, including little or no induction of the cell wall stress stimulon. However, there were a significant number of genes induced by both CCCP and daptomycin that were not induced by oxacillin or vancomycin, such that the daptomycin transcriptome was probably reflecting a membrane depolarizing activity of this antimicrobial also. The results indicate that inhibition of peptidoglycan biosynthesis, either directly or indirectly, and membrane depolarization are parts of the mode of action of daptomycin. Keywords: mode of action, transcriptional profiling
2007-12-25 | GSE9494 | GEO
Project description:Daptomycin is a membrane-targeting last-resort antimicrobial therapeutic for the treatment of infections caused by methicillin- and/or vancomycin-resistant Staphylococcus aureus. In the rare event of failed daptomycin therapy, the source of resistance is often attributable to mutations directly within the membrane phospholipid biosynthetic pathway of S. aureus or in the regulatory systems that control cell envelope response and membrane homeostasis. Here we describe the structural changes to the cell envelope in a daptomycin-resistant isolate of S. aureus strain N315 that has acquired mutations in the genes most commonly reported associated with daptomycin resistance: mprF, yycG, and pgsA. In addition to the decreased phosphatidylglycerol (PG) levels that are the hallmark of daptomycin resistance, the mutant with high-level daptomycin resistance had increased branched-chain fatty acids (BCFAs) in its membrane lipids, increased membrane fluidity, and increased cell wall thickness. However, the successful utilization of isotope-labeled straight-chain fatty acids (SCFAs) in lipid synthesis suggested that the aberrant BCFA:SCFA ratio arose from upstream alteration in fatty acid synthesis rather than a structural preference in PgsA. RT-qPCR studies revealed that expression of pyruvate dehydrogenase (pdhB) was suppressed in the daptomycin-resistant isolate, which is known to increase BCFA levels. While complementation with an additional copy of pdhB had no effect, complementation of the pgsA mutation resulted in increased PG formation, reduction in cell wall thickness, restoration of normal BCFA levels, and increased daptomycin susceptibility. Collectively, these results demonstrate that pgsA contributes to daptomycin resistance through its influence on membrane fluidity and cell wall thickness, in addition to phosphatidylglycerol levels.
2023-04-12 | MSV000091690 | MassIVE
Project description:Corynebacterium striatum BM4687
| PRJEB8812 | ENA
Project description:Clinical Case Report
| PRJEB101432 | ENA
Project description:Several groups have shown that through evolution experiments, tolerance and resistance evolved rapidly under cyclic antibiotic treatment. In other words, intermittent antibiotic exposure performed in a typical adaptive laboratory evolution (ALE) experiments will “train” the bacteria to become tolerant/resistant to the drug. Using this experimental strategy, we performed in vitro laboratory evolution in MRSA using daptomycin, and mine novel daptomycin tolerance and resistance mutants, which were isolated at specific time points during the evolution experiments. Three daptomycin-tolerant isolates with different tolerance level were generated from our laboratory evolution (TOL2 and TOL5 with a mild-tolerance phenotype, and TOL6 with a high-tolerance phenotype). They all bear mutations at different genes, and have no increase in MIC towards daptomycin. Besides, we also isolated three daptomycin-resistant isolates (RES1, RES2, RES3) that have a single point mutation in the same gene, mprF, but at different locations, leading to an increased MIC towards daptomycin. Through proteomics, we uncovered the differential adaptation strategies of these daptomycin tolerant and resistant MRSA strains, and how they respond differently to antibiotics compared to the ancestral wild-type.
2022-07-14 | PXD026741 | Pride