Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus

Payne, Jennifer A. E.; Tailhades, Julien; Ellett, Felix; Kostoulias, Xenia; Fulcher, Alex J.; Fu, Ting; Leung, Ryan; Louch, Stephanie; Tran, Alisia G. T. T.; Weber, Severin A.; Schittenhelm, Ralf B.; Lieschke, Graham J.; Qin, Chong; Irima, Daniel; Peleg, Anton Y.; Cryle, Max J.

doi:10.1038/s41467-021-26244-5

Cited by 19 publications

(12 citation statements)

References 69 publications

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“…5 B, quantification revealed that the bacterial abundance in both the 25 mg/ml and 50 mg/ml groups decreased to less than 20% of that in the control group, indicating that the growth of MRSA was suppressed in vivo. As a previous study reported, some antibacterial drugs could improve the recruitment and engulfment of neutrophils in the infection area, which promoted the killing of S. aureus 14 . Therefore, the suppression of MRSA could contribute to the increased phagocytosis and clearance of S. aureus by the increasingly infiltrated inflammatory cells.…”

Section: Resultsmentioning

confidence: 85%

Tranexamic acid protects against implant-associated infection by reducing biofilm formation

Wang

Zhang

et al. 2022

Sci Rep

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Perioperative administration of tranexamic acid (TXA) is thought to be related to decreased postoperative implant-associated infection rates; however, the relationship remains unclear. We explored the inhibitory effect of TXA on infection both in vitro and in vivo. We investigated biofilm formation after TXA administration through different detection methods, all of which showed that TXA reduces biofilm formation in vitro and was further proven to be associated with decreased protein and polysaccharide contents in biofilms. We observed decreased biofilm on implants and decreased bacteria in the infection area with strengthened neutrophil accumulation in the mouse implant-associated infection model. Our results suggest that TXA protects against implant-associated infection by reducing biofilm formation in infected tissues.

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Section: Resultsmentioning

confidence: 85%

Tranexamic acid protects against implant-associated infection by reducing biofilm formation

Wang

Zhang

et al. 2022

Sci Rep

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“…One example is the discovery of “antibiotic‐chemoattractants”, a recombinant antibacterial peptide consisting of vancomycin and pathogen‐associated neutrophil chemoattractant, with the ability to prevent S. aureus infection through targeted activation of the immune system. [ 31 ] In this covalently linked complex, vancomycin functions as a targeting agent with the ability to bind the S. aureus cell wall and kill bacteria, and chemoattractants recruit neutrophils to the surroundings of bacteria, which effectively enhances bacterial clearance. However, the attachment of the two molecules may lead to a significant loss of their own activity, which could lead to poor therapeutic activity, more optimum exploration might be needed.…”

Section: Discussionmentioning

confidence: 99%

A Dual‐Action Molecule Suppresses S. aureus Infection as an Inhibitor Targeting Hla Pore Formation and TLR2 Signaling

Wang

Jiang

et al. 2022

Advanced Biology

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including pneumonia, sepsis and meningitis, and other chronic infections. [1] Novel antibiotics are the most favorable choice, however, the lack of innovative antibiotic development coupled with the frequent emergence of resistant strains may send us back to a preantibiotic era. Increasing evidence suggests that the excessive use of broad-spectrum antibiotics is associated with the risk of many metabolic and inflammatory diseases and some potential diseases related to the disruption of microbiota. [2][3] The rising prevalence of multidrug-resistant and highly virulent strains increases the urgent need for new therapies independent of antibacterial activity.S. aureus produces diverse exotoxins to facilitate its colonization and spreading during infection, and one of the most well-characterized exotoxins is Hla, a typical β-barrel pore-forming cytotoxin expressed by almost all clinical isolates. [4] Hla plays indispensable role in the pathogenesis of invasive infections, phagosome escape, and partially the triggering of the immune response. [5] Hla-induced activation of a disintegrin and metalloproteinase 10 is a critical mechanism of barrier disruption that greatly contributes to the pathogenesis of lethal S. aureus infections by enabling effective spreading. [6] Hla pore-dependent activation of NOD-like receptor protein 3 inflammasome is a successful example of pathogens exploiting host inflammatory signaling by enhancing the pathogenesis of severe S. aureus infection via inducing necrosis. [7] Moreover, Hla is exploited to manipulate adaptive immunity against S. aureus, suppressing the antigen-specific memory T cell response by disturbing DC-T cell crosstalk. [8] Notably, the pore formation activity of Hla is required for these cellular events as the inactive mutant H35L retains the ability to bind the membrane while impaired pore formation fails to act in these cases. The critical role of Hla in S. aureus pathogenesis renders it a developing therapeutic target for virulence-specific strategies aiming to attenuate the pathogenicity of S. aureus rather than directly kill bacteria.Host innate immune response is the first line of defense against S. aureus infection, promoting bacterial clearance and limiting the inciting injury of infection and systemic spreading through neutrophil chemotaxis, phagocytosis and inflammation. [9] However, inflammation is a double-edged sword. In most Antibiotic resistance is the greatest challenge for the treatment of Staphylococcus aureus (S. aureus) infection under the global antibiotic resistance crisis. With the bottleneck period of the development of new antibiotics, novel alternative agents are urgently in need. In this study, the small molecule amentoflavone is identified as a dual-action inhibitor of Hla, a pore-forming virulence determinant particularly important for S. aureus pathogenicity and Toll-like receptor 2 (TLR2) signaling, which triggers inflammation response upon recognizing pathogen-associated molecular patterns. Amentoflavone treatment conferred effective protec...

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“…shown by fusion of an antibiotic-targeting element with an FPR agonist, which enhances neutrophil clearance, providing a viable immunotherapeutic strategy to treat resistant S. aureus infections (Payne et al, 2021).…”

Section: Indications For Fpr2-targeted Therapiesmentioning

confidence: 99%

“…Evidence for FPR2‐targeted therapies for each of these indications has been obtained from exogenous administration of peptides derived from endogenous FPR agonists, such as ANXA1 or its cleavage products, blunting inflammatory responses (and/or with a monoclonal antibody to these, in which an exacerbated inflammatory response was evident) (Vital et al, 2020; Wu et al, 2021; Yang et al, 1997, 1999), exogenous small‐molecule FPR agonists (Borgeson et al, 2015; Brennan, Mohan, McClelland, de Gaetano, et al, 2018; Kain et al, 2017; Petri et al, 2017; Qin et al, 2017; Schottelius et al, 2002) or FPR2‐deficient mice (Chen et al, 2019; Petri et al, 2017; Petri et al, 2018; Tourki, Kain, Pullen, et al, 2020; Tourki, Kain, Shaikh, et al, 2020). Lastly, given the importance of FPR2 in myeloid cell trafficking during infection and inflammation, FPRs could be used to develop novel therapeutic approaches for antibiotic development, as shown by fusion of an antibiotic‐targeting element with an FPR agonist, which enhances neutrophil clearance, providing a viable immunotherapeutic strategy to treat resistant S. aureus infections (Payne et al, 2021).…”

Section: Indications For Fpr2‐targeted Therapiesmentioning

confidence: 99%

Formylpeptide receptor 2: Nomenclature, structure, signalling and translational perspectives: IUPHAR review 35

Qin

Norling

Vecchio

et al. 2022

British J Pharmacology

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We discuss the fascinating pharmacology of formylpeptide receptor 2 (FPR2; often referred to as FPR2/ALX since it binds lipoxin A4). Initially identified as a low‐affinity ‘relative’ of FPR1, FPR2 presents complex and diverse biology. For instance, it is activated by several classes of agonists (from peptides to proteins and lipid mediators) and displays diverse expression patterns on myeloid cells as well as epithelial cells and endothelial cells, to name a few. Over the last decade, the pharmacology of FPR2 has progressed from being considered a weak chemotactic receptor to a master‐regulator of the resolution of inflammation, the second phase of the acute inflammatory response. We propose that exploitation of the biology of FPR2 offers innovative ways to rectify chronic inflammatory states and represents a viable avenue to develop novel therapies. Recent elucidation of FPR2 structure will facilitate development of the anti‐inflammatory and pro‐resolving drugs of next decade.

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Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus

Cited by 19 publications

References 69 publications

Tranexamic acid protects against implant-associated infection by reducing biofilm formation

Tranexamic acid protects against implant-associated infection by reducing biofilm formation

A Dual‐Action Molecule Suppresses S. aureus Infection as an Inhibitor Targeting Hla Pore Formation and TLR2 Signaling

Formylpeptide receptor 2: Nomenclature, structure, signalling and translational perspectives: IUPHAR review 35

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