Novel anti-virulence compounds disrupt exotoxin expression in MRSA
Ontology highlight
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: Not available
| S-EPMC11619317 | biostudies-literature
Project description:Previous studies have documented the diversity of genetic background of methicillin-resistant S. aureus (MRSA) strains associated with healthcare (HA-MRSA), community (CA-MRSA) and livestock (LA-MRSA). The accessory and core-variable genome content of those strains remain largely unknown. To compare the composition of accessory and core-variable genome of Belgian MRSA strains according to host, population setting and genetic background, representative strains of HA- (n=21), CA- (n = 13) and ST398 LA-MRSA (n = 18) were characterized by a DNA-microarray (StaphVar Array) composed of oligonucleotide probes targeting ~400 resistance, adhesion and virulence associated genes.ST398 strains displayed very homogenous hybridization profiles (>94% gene content homology) irrespective of their host origin. This “ST398-specific” genomic profile was not distantly demarked from those of certain human-associated lineages but lacked several virulence- and colonization-associated genes harbored by strains of human origin, such as genes encoding proteases, haemolysins or adhesins. No enterotoxin gene was found among ST398 strains. In conclusion, our findings are consistent with a non-human origin of this ST398 lineage but suggest that it might have the potential to adapt further to the human host.
2010-11-15 | GSE20541 | GEO
Project description:Panton-valentine leukocidin (PVL) has been linked to worldwide emergence of community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) -- its role in virulence in unclear. Here we show that PVL had no effect on global gene expression of prominent CA-MRSA strains nor did it affect bacterial clearance from lungs, spleen and kidneys in a highly discriminatory rabbit bacteremia model. These findings negate a large body of epidemiological research that implicated PVL in CA-MRSA virulence. Keywords: mutant vs wild type in 2 different growth phases grown in 2 different medias
2008-09-12 | GSE8677 | GEO
Project description:To examine the impact of virulence determinants in ST72 CA-MRSA isolates, we carried out RNA-seq analysis to compare the transcriptomes of the deletion mutants with that of the wild-type
2019-12-31 | E-MTAB-7809 | biostudies-arrayexpress
Project description:Panton-valentine leukocidin (PVL) has been linked to worldwide emergence of community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) -- its role in virulence in unclear. Here we show that PVL had no effect on global gene expression of prominent CA-MRSA strains nor did it affect bacterial clearance from lungs, spleen and kidneys in a highly discriminatory rabbit bacteremia model. These findings negate a large body of epidemiological research that implicated PVL in CA-MRSA virulence. Keywords: mutant vs wild type in 2 different growth phases grown in 2 different medias Wild type USA 300 (strain SF8300), wild type USA 400 (strain MW2) were compared against their respective PVL isogenic knock out strains. Strains were compared at both mid-exponential and stationary phase and grown in both TSB and CCY to determine if PVL plays a role in gene regulation under these conditions.
2010-06-19 | E-GEOD-8677 | biostudies-arrayexpress
Project description:The success of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) as pathogens is due to a combination of antibiotic resistance with high virulence. However, evolution of the exceptional virulence potential of CA-MRSA is not understood. Our previous study indicated that differential gene expression contributes substantially to this process. Thus, we here investigated the role of the pivotal virulence gene regulatory system agr in the most prevalent CA-MRSA strain USA300. Using a mouse subcutaneous infection model, we show that agr is essential for the development of CA-MRSA skin infections, the most frequent manifestation of disease caused by CA-MRSA. Furthermore, genome-wide analysis of gene expression revealed significant differences in agr-dependent virulence gene regulation between CA-MRSA, HA-MRSA, and laboratory strains. Our findings demonstrate that agr functionality is critical for CA-MRSA disease and indicate that an adaptation of the agr regulon to optimize expression of a broad set of virulence determinants may have contributed to the evolution of exceptionally pronounced virulence of CA-MRSA strains. Keywords: wild type vs mutant
2011-03-29 | GSE18793 | GEO
Project description:Background: Community-associated methicillin-resistant staphylococcus aureus (CA-MRSA) is a drug-resistant bacterium prevalent in community settings, characterized by high pathogenicity and transmission potential. Polymorphonuclear neutrophils (PMNs) represent the first line of defense in innate immunity and are activated to phagocytose MRSA. However, MRSA, once phagocytosed by PMNs, induces necroptosis within the neutrophils, which is a key mechanism contributing to host damage.CA-MRSA releases virulence factors that enhance its pathogenicity by disrupting the host's innate immune response, particularly impairing the phagocytic function of PMNs. Steamed Panax notoginseng (S-PN) has demonstrated immune-regulatory and anti-inflammatory properties, showing promising therapeutic effects in alleviating the severe inflammatory responses induced by pathogenic microbial infections. Objective: This study aims to investigate the pharmacological effects and mechanisms of S-PN in attenuating CA-MRSA-induced necroptosis of PMNs, and to explore the impact of PMN necroptosis on the inflammatory response. Methods: A co-culture model of MRSA USA300 strain and PMNs isolated from healthy human blood was established to observe the changes in necroptosis marker HMGB1, PMNs counts, ROS, chemokine MCP-1 and pro-inflammatory cytokines IL-1β, IL-8, TNF-α. RNA-seq was employed to analyze the effects of S-PN on the transcriptional expression of pathogenesis-related genes of MRSA. RT-PCR was utilized to validate the expression of S-PN on MRSA virulence factors and PMNs necroptosis related genes. Results: S-PN significantly inhibited HMGB1, ROS, MCP-1, IL-1β and IL-8 in MRSA-PMN co-cultures, the PMN count in the S-PN group was higher than that in the model group. S-PN down-regulated MRSA pathogenic-associated Staphylococcus aureus infection and quorum sensing signaling pathways, and significantly reduced the virulence factors PSM and PVL. S-PN suppressed the expression of genes associated with necroptosis ripk1, ripk3, and mlkl in PMNs. Conclusion: S-PN inhibited CA-MRSA-induced necroptosis of PMNs, as well as the excessive inflammatory response and ROS accumulation accompanying this process. The mechanism involves the inhibition of the expression of MRSA virulence factor PSM and necroptosis pathway genes. These findings underscore the significant potential of S-PN in the treatment of CA-MRSA infections.
2025-03-19 | GSE284429 | GEO
Project description:The success of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) as pathogens is due to a combination of antibiotic resistance with high virulence. However, evolution of the exceptional virulence potential of CA-MRSA is not understood. Our previous study indicated that differential gene expression contributes substantially to this process. Thus, we here investigated the role of the pivotal virulence gene regulatory system agr in the most prevalent CA-MRSA strain USA300. Using a mouse subcutaneous infection model, we show that agr is essential for the development of CA-MRSA skin infections, the most frequent manifestation of disease caused by CA-MRSA. Furthermore, genome-wide analysis of gene expression revealed significant differences in agr-dependent virulence gene regulation between CA-MRSA, HA-MRSA, and laboratory strains. Our findings demonstrate that agr functionality is critical for CA-MRSA disease and indicate that an adaptation of the agr regulon to optimize expression of a broad set of virulence determinants may have contributed to the evolution of exceptionally pronounced virulence of CA-MRSA strains. Keywords: wild type vs mutant Wild type vs mutant agr strains.
2011-03-29 | E-GEOD-18793 | biostudies-arrayexpress
Project description:Cryptococcus neoformans is a human fungal pathogen responsible for fatal infections, especially in patients with a depressed immune system. Overexposure to antifungal drugs due to prolonged treatment regimens and structure-similar applications in agriculture have weakened the efficacy of current antifungals in the clinic. The rapid evolution of antifungal resistance urges the discovery of new compounds that inhibit fungal virulence factors, rather than directly killing the pathogen as alternative strategies to overcome disease and reduce selective pressure towards resistance. Recent studies, including our own, have highlighted the antimicrobial properties of natural sources, such as invertebrates, against human fungal pathogens, including C. neoformans, through virulence factor impairment. Here, we evaluated the efficacy of freshwater mussel extracts (crude and clarified) against virulence factor production (i.e., thermotolerance, melanin, capsule, and biofilm) in C. neoformans. Similarly, we demonstrated the critical potential of these extracts to increase the susceptibility of the pathogen to fluconazole across resistant strains, overcoming a globally devastating problem. Additionally, we measured the inhibitory activity of the extracts against peptidases related to fungal virulence and drug resistance. Furthermore, we integrated these phenotypic findings with quantitative proteomics profiling to define distinct signatures of each treatment and validated a new mechanism of anti-virulence action for a selected extract. By understanding the mechanisms driving the antifungal activity of mussels, we may develop innovative treatments for fungal infections lacking susceptibility to conventional drugs.
2024-01-27 | PXD043643 | Pride