Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus

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

doi:10.1038/s41467-021-26244-5

Abstract

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 antibiotic vancomycin (known to bind to the bacterial cell wall). We use a combination of in vitro assays, cellular assays, infection-on-a-chip and in vivo mouse models to show that the compounds improve the recruitment, engulfment and killing of S. aureus by neutrophils. Furthermore, optimizing the formyl peptide sequence can enhance neutrophil activity through differential activation of formyl peptide receptors. Thus, we propose antibiotic-chemoattractants as an alternate approach for antibiotic development.

Highlights

The pathogen Staphylococcus aureus can readily develop antibiotic resistance and evade the human immune system, which is associated with reduced levels of neutrophil recruitment
Vancomycin was chosen as the optimal candidate for our antibiotic-chemoattractant approach, as its mechanism of action involves binding to the bacterial surface[19,20]
Conjugate binding was observed to B. subtilis, suggesting the potential for antibiotic-chemoattracts to be used against Grampositive bacteria more generally; no binding was observed to E. coli (B1, Supplementary Fig. 2)

Summary

Introduction

The pathogen Staphylococcus aureus can readily develop antibiotic resistance and evade the human immune system, which is associated with reduced levels of neutrophil recruitment. The ability of antibiotic-resistant bacteria to avoid immune detection can be overcome using these dual-acting molecules by enhancing the chemoattractant gradient around the bacteria The establishment of this gradient is an essential step for the recruitment of innate immune cells, such as neutrophils, for prevention, and resolution of infection. These fPeps are the N-terminal fragments of bacterial proteins, as formyl methionine initiates protein biosynthesis in bacteria[13,15] These bacterially derived peptides are strong inducers of chemotaxis and are necessary for neutrophils to mount a successful immune response; host-derived chemoattractants alone often insufficient for this task[16,17]. To provide specificity of immune activation toward the infecting bacteria, a chemotactic agent combined with a bacterial targeting component is necessary

Methods

Results

Conclusion