Dataset Information

Antibiotic-Chemoattractants Enhance Neutrophil Clearance of Staphylococcus aureus

ABSTRACT: S. aureus is a deadly pathogen due to its abilities to readily develop antibiotic resistance and evade our immune system. Antibiotic resistance in S. aureus is associated with reduced levels of neutrophil recruitment, which is a vital step in triggering an immune response to resolve infection. In this work, we report enhanced antibiotic agents that act as potential dual-function antibiotic-chemoattractants, enabling augmented neutrophil recruitment to S. aureus along with direct killing. Our agents exploit formylated peptides as chemoattractants for neutrophil recruitment, which is combined with the targeted binding of vancomycin to bacteria that generates a chemoattractant gradient for neutrophil recruitment. The combination of in vitro assays, cellular assays, infection-on-a-chip and in vivo mouse models, determined that these antibiotic-chemoattractants improve the recruitment, engulfment and killing of S. aureus by neutrophils. Furthermore, optimizing the fPep sequence can play an important role in the enhancement of neutrophil activity through differential activation of formyl peptide receptors. This offers an alternate approach in antibiotic development to overcome the threat of antibiotic resistance in the clinic.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Ralf Schittenhelm

LAB HEAD: Max J Cryle

PROVIDER: PXD028332 | Pride | 2021-09-22

REPOSITORIES: Pride

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Publications

Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus.

Payne Jennifer A E JAE Tailhades Julien J Ellett Felix F Kostoulias Xenia X Fulcher Alex J AJ Fu Ting T Leung Ryan R Louch Stephanie S Tran Amy A Weber Severin A SA Schittenhelm Ralf B RB Lieschke Graham J GJ Qin Chengxue Helena CH Irima Daniel D Peleg Anton Y AY Cryle Max J MJ

Nature communications 20211025 1

The pathogen Staphylococcus aureus can readily develop antibiotic resistance and evade the human immune system, which is associated with reduced levels of neutrophil recruitment. Here, we present a class of antibacterial peptides with potential to act both as antibiotics and as neutrophil chemoattractants. The compounds, which we term 'antibiotic-chemoattractants', consist of a formylated peptide (known to act as chemoattractant for neutrophil recruitment) that is covalently linked to the antibi ...[more]

PMID: 34697316

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Project description:Staphylococcus aureus is one of the first and most prevalent pathogens cultured from the airways of cystic fibrosis (CF) patients, which can persist there for extended periods. Airway infections in CF patients are characterized by a strong inflammatory response of highly recruited neutrophils. One killing mechanism of neutrophils is the formation of neutrophil extracellular traps (NETs), which capture and eradicate bacteria by extracellular fibers of neutrophil chromatin decorated with antimicrobial granule proteins. S. aureus secretes nuclease, which can degrade NETs. We hypothesized, that S. aureus adapts to the airways of CF patients during persistent infection by escaping from NET-mediated killing via an increase of nuclease activity. Sputum samples of CF patients with chronic S. aureus infection were visualized by confocal microscopy after immuno-fluorescence staining for NET-specific markers, S. aureus bacteria and overall DNA structures. Nuclease activity was analyzed in sequential isogenic long persisting S. aureus isolates, as confirmed by whole genome sequencing, from an individual CF patient using a FRET-based nuclease activity assay. Additionally, some of these isolates were selected and analyzed by qRT-PCR to determine the expression of nuc1 and regulators of interest. NET-killing assays were performed with clinical S. aureus isolates to evaluate killing and bacterial survival depending on nuclease activity. To confirm the role of nuclease during NET-mediated killing, a clinical isolate with low nuclease activity was transformed with a nuclease expression vector (pCM28nuc). Furthermore, two sputa from an individual CF patient were subjected to RNA-sequence analysis to evaluate the activity of nuclease in vivo. In sputa, S. aureus was associated to extracellular DNA structures. Nuclease activity in clinical S. aureus isolates increased in a time-and phenotype-dependent manner. In the clinical isolates, the expression of nuc1 was inversely correlated to the activity of agr and was independent of saeS. NET-mediated killing was significantly higher in S. aureus isolates with low compared to isolates with high nuclease activity. Importantly, transformation of the clinical isolate with low nuclease activity with pCM28nuc conferred protection against NET-mediated killing confirming the beneficial role of nuclease for protection against NETs. Also, nuclease expression in in vivo sputa was high, which underlines the important role of nuclease within the highly inflamed CF airways. In conclusion, our data show that S. aureus adapts to the neutrophil-rich environment of CF airways with increasing nuclease expression most likely to avoid NET-killing during long-term persistence.

Dataset Information

Antibiotic-Chemoattractants Enhance Neutrophil Clearance of Staphylococcus aureus

Publications

Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus.

Similar Datasets

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