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The polyaminoisoprenyl compound NV716 re-sensitizes antibiotics against Pseudomonas aeruginosa by perturbing outer membrane permeability and reduces bacterial virulence.

ABSTRACT: The polyaminoisoprenyl compound NV716 re-sensitizes antibiotics against Pseudomonas aeruginosa by perturbing outer membrane permeability and reduces bacterial virulence.

PROVIDER: PRJNA786237 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17133404_1.fastq.gz	Fastqsanger.gz
	SRR17133404_2.fastq.gz	Fastqsanger.gz
	SRR17133405_1.fastq.gz	Fastqsanger.gz
	SRR17133405_2.fastq.gz	Fastqsanger.gz
	SRR17133406_1.fastq.gz	Fastqsanger.gz

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The polyaminoisoprenyl compound NV716 re-sensitizes antibiotics against Pseudomonas aeruginosa by perturbing outer membrane permeability and reduces bacterial virulence.

Project description:Objective: to determine the changes in transcriptome induced by exposure during 52 successive passages of PAO1 to membrane-active agents, namely colistin (CST), alexidine (ALE) and NV716, an investigation polyamino-isoprenic compound Methods: PAO1 was exposed during 50 passages to each of these agents at 1/2 MIC, after which , cells were harvested, and RNA was purified and analyzed by RNAseq Results: upregulations of genes involved in lipidA/LPS synthesis as well as downrelgulation of genes involved in virulence were observed with NV716. Changes in genes related to LipidA and LPS synthesis were also observed with the other agents. Conclusion: Our results provide new insights into the mechanism of action of NV716 and potential targets in P. aeruginosa.

2022-08-31 | GSE190194 | GEO

Acetylome reveals the lysine acetylation modifications on outer membrane protein Aha1 in Aeromonas hydrophila regulate the porin permeability to multidrug antibiotics

Project description:Acetylome reveals the lysine acetylation modifications on outer membrane protein Aha1 in Aeromonas hydrophila regulate the porin permeability to multidrug antibiotics

2022-04-28 | PXD028447 |

Role of SurA, BamB, BamC and HlpA for shaping the outer membrane protein composition of Pseudomonas aeruginosa

Project description:Pseudomonas aeruginosa (Pa) is one of the main causative agents of nosocomial infections and the spread of multidrug-resistant strains is rising. The outer membrane composition of Pa restricts antibiotic entry and determines virulence. For efficient outer membrane protein biogenesis, the BAM complex and chaperones like Skp and SurA are crucial. Deletion mutants of bamB, bamC and the skp homolog hlpA as well as a conditional mutant of surA were investigated. The most profound effects were associated with a lack of SurA, characterized by increased membrane permeability, enhanced sensitivity to antibiotic treatment and attenuation of virulence in a Galleria mellonella infection model. Strikingly, the conditional deletion of surA in a multidrug-resistant bloodstream isolate re-sensitized the strain to antibiotic treatment. Mass spectrometry revealed striking alterations in the outer membrane composition. Thus, SurA of Pa is important for the insertion of many porins, type V secretion systems, TonB-dependent receptors, proteins involved in LPS transport and BAM complex components. Therefore, SurA of Pa serves as a promising target for developing a drug that shows antiinfective activity and sensitizes multidrug-resistant strains to antibiotics.

2019-03-12 | PXD011849 | Pride

Prostaglandin E2 stimulates opposing effects on inner and outer blood-retina barrier function

Project description:Diabetic retinopathy (DR) is the leading cause of vision loss in working-age individuals globally, and the associated complication of diabetic macular edema (DME) is the most frequent cause of vision loss in these patients. The retinal swelling characteristic of DME can be attributed to fluid leakage due to damage to the two blood-retina barriers—the inner barrier composed primarily of retinal microvascular endothelial cells and the outer barrier composed of retinal pigment epithelial cells (RPE). Based on the previously characterized proinflammatory roles of prostanoid signaling in DR, we assayed the distinct prostanoid signaling mechanisms regulating inner and outer blood-retina barrier function using in vitro methods involving monoculture of primary human cells. Prostaglandin E2 (PGE2) stimulation of retinal endothelial monolayers caused a decrease in barrier permeability in electric cell-substrate impedance sensing (ECIS) assays and dextran flux assays. These effects occurred specifically via the EP4 receptor of PGE2. In direct contrast, PGE2 stimulation of RPE monolayers caused an increase in barrier permeability via the EP2 receptor. Other prostanoids did not alter barrier permeability in either monocellular model. RNA sequencing of retinal endothelial and RPE cells with or without PGE2 stimulation revealed significant dysregulation of genes encoding junctional complex components and signaling that likely drive the observed effects on cell barrier resistance. Together these results identify opposing mechanisms of PGE2 signaling in the retina via two distinct receptors, indicating cell type-specific and receptor-specific targets for the potential therapeutic management of DME or other causes of dysfunctional retinal vascular permeability.

2025-10-01 | GSE301373 | GEO

Activation of Piezo1 sensitizes cells to TRAIL-mediated apoptosis through mitochondrial outer membrane permeability.

Project description:TRAIL specifically induces apoptosis in cancer cells without affecting healthy cells. However, TRAIL's cancer cytotoxicity was insufficient in clinical trials. Circulatory-shear stress is known to sensitize cancer cells to TRAIL. In this study, we examine the mechanism of this TRAIL sensitization with the goal of translating it to static conditions. GsMTx-4, a Piezo1 inhibitor, was found to reduce shear stress-related TRAIL sensitization, implicating Piezo1 activation as a potential TRAIL-sensitizer. The Piezo1 agonist Yoda1 recreated shear stress-induced TRAIL sensitization under static conditions. A significant increase in apoptosis occurred when PC3, COLO 205, or MDA-MB-231 cells were treated with Yoda1 and TRAIL in combination, but not in Bax-deficient DU145 cells. Calpastatin inhibited apoptosis in Yoda1-TRAIL treated cells, indicating that calpain activation is necessary for apoptosis by Yoda1 and TRAIL. Yoda1 and TRAIL treated PC3 cells showed increased mitochondrial outer membrane permeability (MOMP), mitochondrial depolarization, and activated Bax. This implies that Piezo1 activation sensitizes cancer cells to TRAIL through a calcium influx that activates calpains. The Calpains then induce MOMP by enhancing Bax activation. From these experiments a computational model was developed to simulate apoptosis for cells treated with TRAIL and increased calcium. The computational model elucidated the proapoptotic or antiapoptotic roles of Bax, Bcl-2, XIAP, and other proteins important in the mitochondrial-apoptotic signaling pathway.

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A host-directed adjuvant sensitizes intracellular bacterial persisters to antibiotics

Project description:Intracellular bacterial reservoirs contribute to antibiotic treatment failure by fostering metabolically dormant persister cells that are highly tolerant to killing. However, strategies to effectively target intracellular persister cells remain limited. Here, we developed a high-throughput screen to identify compounds that modulate the metabolic activity of intracellular Staphylococcus aureus. The identified compound, KL1, increases intracellular bacterial metabolic activity and sensitizes persister populations of S. aureus to antibiotics, without causing cytotoxicity or bacterial outgrowth. KL1 also exhibits adjuvant activity against intramacrophage Salmonella enterica Typhimurium and Mycobacterium tuberculosis, as well as in murine infection models of S. aureus and S. Typhimurium infection. Transcriptomic analysis and further mechanistic studies reveal that KL1 modulates host immune response genes and suppresses the production of reactive species in host macrophages, alleviating a key inducer of antibiotic tolerance. Our findings highlight the potential to target intracellular persisters by stimulating their metabolism.

2025-08-01 | GSE280093 | GEO

Complement-dependent outer membrane perturbation sensitizes Gram-negative bacteria to Gram-positive specific antibiotics.

Project description:Gram-negative bacteria are refractory to the action of many antibiotics due to their impermeable outer membrane. An important player of the immune system is the complement system, a protein network in serum that directly kills Gram-negative bacteria through pore-formation by the Membrane Attack Complexes (MAC). We here show that the MAC rapidly perforates the outer membrane but that inner membrane damage, which is essential for killing, is relatively slow. Importantly, we demonstrate that MAC-induced outer membrane damage sensitizes Gram-negative bacteria to otherwise ineffective, Gram-positive-specific, antimicrobials. Synergy between serum and nisin was observed for 22 out of 53 tested Gram-negative clinical isolates and for multi-drug resistant (MDR) blood isolates. The in vivo relevance of this process is further highlighted by the fact that blood sensitizes a MDR K. pneumoniae strain to vancomycin. Altogether, these data imply that antibiotics that are considered ineffective to treat infections with Gram-negatives may have different functional outcomes in patients, due to the presence of the complement system.

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