Novel anti-virulence compounds disrupt exotoxin expression in MRSA
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ABSTRACT:
PROVIDER: PRJNA1109356 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28966336_1.fastq.gz | Fastqsanger.gz | |||
| SRR28966336_2.fastq.gz | Fastqsanger.gz | |||
| SRR28966337_1.fastq.gz | Fastqsanger.gz | |||
| SRR28966337_2.fastq.gz | Fastqsanger.gz | |||
| SRR28966338_1.fastq.gz | Fastqsanger.gz |
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Project description:Hemolysins are lytic exotoxins expressed in most strains of S. aureus, but hemolytic activity varies between strains. We have previously reported several novel anti-virulence compounds that disrupt the S. aureus transcriptome, including hemolysin gene expression. This report delves further into our two lead compounds, loratadine and a structurally related brominated carbazole, and their effects on hemolysin production in methicillin-resistant S. aureus (MRSA). To gain understanding into how these compounds affect hemolysis, we analyzed these exotoxins at the DNA, RNA, and protein level after in vitro treatment. While lysis of red blood cells varied between strains, DNA sequence variation did not account for it. We hypothesized that our compounds would modulate gene expression of multiple hemolysins in two hospital-acquired strains of MRSA, both with staphylococcal cassette chromosome mec (SCCmec) type II. RNA-seq analysis of differential gene expression in untreated and compound-treated cultures revealed hundreds of differentially expressed genes, with a significant enrichment in genes involved in hemolysis. The brominated carbazole and loratadine both displayed the ability to reduce hemolysis in strain 43300 but displayed differential activity in strain USA100. These results corroborate gene expression studies as well as western blots of alpha hemolysin. Together, this work suggests that small molecules may alter exotoxin production in MRSA but that the directionality and/or magnitude of the difference are likely strain dependent.
2024-05-15 | GSE267020 | GEO
Project description:Hemolysins are lytic exotoxins expressed in most strains of S. aureus, but hemolytic activity varies between strains. We have previously reported several novel anti-virulence compounds that disrupt the S. aureus transcriptome, including hemolysin gene expression. This report delves further into our two lead compounds, loratadine and a structurally related brominated carbazole, and their effects on hemolysin production in methicillin-resistant S. aureus (MRSA). To gain understanding into how these compounds affect hemolysis, we analyzed these exotoxins at the DNA, RNA, and protein level after in vitro treatment. While lysis of red blood cells varied between strains, DNA sequence variation did not account for it. We hypothesized that our compounds would modulate gene expression of multiple hemolysins in two hospital-acquired strains of MRSA, both with staphylococcal cassette chromosome mec (SCCmec) type II. RNA-seq analysis of differential gene expression in untreated and compound-treated cultures revealed hundreds of differentially expressed genes, with a significant enrichment in genes involved in hemolysis. The brominated carbazole and loratadine both displayed the ability to reduce hemolysis in strain 43300 but displayed differential activity in strain USA100. These results corroborate gene expression studies as well as western blots of alpha hemolysin. Together, this work suggests that small molecules may alter exotoxin production in MRSA but that the directionality and/or magnitude of the difference are likely strain dependent.IMPORTANCEMethicillin-resistant S. aureus (MRSA) is a deadly human pathogen. In addition to evading antibiotics, these bacteria produce a wide range of toxins that negatively affect the host. Our work aims to identify and characterize novel compounds that can decrease the pathogenic effects of MRSA. Two lead compounds investigated in this study triggered changes in the production of multiple toxins. These changes were specific to the strain of MRSA investigated. Specifically, this work sheds light on novel compounds that decrease MRSA's ability to lyse host red blood cells. Importantly, it also highlights the importance of examining strain-specific differences in response to therapeutic interventions that could ultimately affect clinical outcomes.
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Project description:Heterochromatin plays a key role in gene repression, maintaining genome integrity and chromosome segregation. Fission yeast, Schizosaccharomyces pombe, utilizes conserved components to direct heterochromatin formation using siRNA generated by RNA interference (RNAi) to guide a histone H3 lysine 9 methyltransferase to cognate chromatin. To identify compounds that inhibit heterochromatin formation, an in vivo phenotypic screen for loss of silencing was performed. A tester strain harbouring a silent dominant selectable kanMX reporter gene within fission yeast centromeric heterochromatin was used to screen a diverse library of chemicals. HMS-I1 and HMS-I2 were identified as compounds that reproducibly increased G418 resistance due to loss of kanMX silencing, and decreased the level of repressive H3K9 methylation on centromeric repeats. The pattern of changes induced by HMS-I1 and HMS-I2 were consistent with inhibition of the histone deacetylases (HDACs) Clr3 and/or Sir2. Chemical-genetic interactions and expression profiling indicated that both HMS-I1 and HMS-I2 affect the activity of the Clr3-containing Snf2/HDAC repressor complex (SHREC). Exposure to HMS-I1 was also found to alleviate silencing of reporter genes in an Arabidopsis transgenic plant line and a mouse cell line. HMS-I2 also disrupted reporter gene silencing in Arabidopsis. In vitro assays indicate that HMS-I1 impairs the activity of human HDAC6 and HDAC10. As HMS-I1 and HMS-I2 bear no resemblance to known inhibitors of chromatin-based activities they represent potentially novel and valuable reagents for experimental and therapeutic purposes. Our findings highlight the use of in vivo chemical screening conducted in fission yeast to identify compounds that disrupt heterochromatin across plant, fungi and animal kingdoms. 16 RNA samples: 2 replicates of WT untreated (vehicle DMSO) (KE1-A, KE2-A), HMS-I1 treated (KE1-B, KE2-B), HMS-I2 treated (KE1-C, KE2-C), and 2 additional replicates of WT (KE05_wt_1, KE10_wt_2), 4 replicates of clr2M-bM-^HM-^F (KE01_2118_1, KE06_2118_2, KE03_0080_1, KE08_0080_2) and mit1M-bM-^HM-^F (KE02_1295_1, KE07_1295_2, KE04_1278_1, KE09_1278_2).
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Project description:A screen of 5 anti-inflammatory compounds for their effects in explanted, cultured rat spinal cord slices. All injured (explanted) cords are cultured for 4 hrs. Keywords: ordered
2003-10-03 | GSE633 | GEO
Project description:Heterochromatin plays a key role in gene repression, maintaining genome integrity and chromosome segregation. Fission yeast, Schizosaccharomyces pombe, utilizes conserved components to direct heterochromatin formation using siRNA generated by RNA interference (RNAi) to guide a histone H3 lysine 9 methyltransferase to cognate chromatin. To identify compounds that inhibit heterochromatin formation, an in vivo phenotypic screen for loss of silencing was performed. A tester strain harbouring a silent dominant selectable kanMX reporter gene within fission yeast centromeric heterochromatin was used to screen a diverse library of chemicals. HMS-I1 and HMS-I2 were identified as compounds that reproducibly increased G418 resistance due to loss of kanMX silencing, and decreased the level of repressive H3K9 methylation on centromeric repeats. The pattern of changes induced by HMS-I1 and HMS-I2 were consistent with inhibition of the histone deacetylases (HDACs) Clr3 and/or Sir2. Chemical-genetic interactions and expression profiling indicated that both HMS-I1 and HMS-I2 affect the activity of the Clr3-containing Snf2/HDAC repressor complex (SHREC). Exposure to HMS-I1 was also found to alleviate silencing of reporter genes in an Arabidopsis transgenic plant line and a mouse cell line. HMS-I2 also disrupted reporter gene silencing in Arabidopsis. In vitro assays indicate that HMS-I1 impairs the activity of human HDAC6 and HDAC10. As HMS-I1 and HMS-I2 bear no resemblance to known inhibitors of chromatin-based activities they represent potentially novel and valuable reagents for experimental and therapeutic purposes. Our findings highlight the use of in vivo chemical screening conducted in fission yeast to identify compounds that disrupt heterochromatin across plant, fungi and animal kingdoms.
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