Linear peptidomimetics as potent antagonists of Staphylococcus aureus agr quorum sensing

Abstract

Staphylococcus aureus is an important pathogen causing infections in humans and animals. Increasing problems with antimicrobial resistance has prompted the development of alternative treatment strategies, including antivirulence approaches targeting virulence regulation such as the agr quorum sensing system. agr is naturally induced by cyclic auto-inducing peptides (AIPs) binding to the AgrC receptor and cyclic peptide inhibitors have been identified competing with AIP binding to AgrC. Here, we disclose that small, linear peptidomimetics can act as specific and potent inhibitors of the S. aureus agr system via intercepting AIP-AgrC signal interaction at low micromolar concentrations. The corresponding linear peptide did not have this ability. This is the first report of a linear peptide-like molecule that interferes with agr activation by competitive binding to AgrC. Prospectively, these peptidomimetics may be valuable starting scaffolds for the development of new inhibitors of staphylococcal quorum sensing and virulence gene expression.

Investigating the Mechanism of Action of Diketopiperazines Inhibitors of the Burkholderia cenocepacia Quorum Sensing Synthase CepI: A Site-Directed Mutagenesis Study

“…Quorum sensing inhibitors appear as very promising potentiators of the classical antibiotic therapy to treat dangerous infections such as those caused by B. cenocepacia , for which a lack of new solutions is massively reported ( Horsley et al, 2011 ; Regan and Bhatt, 2016 ; Scoffone et al, 2017 ). Searching in PubMed for “quorum sensing inhibitors” retrieves 51 results in the first 5 months of 2018, which shows the increasing interest in alternative routes to counteract the emergence of resistance among bacteria such as Proteus mirabilis ( Yu et al, 2018 ), Salmonella ( de Almeida et al, 2018 ), Pseudomonas aeruginosa ( Almohaywi et al, 2018 ), Staphylococcus aureus ( Karathanasi et al, 2018 ).…”

New Approaches for Competing Microbial Resistance and Virulence

“…Solonamide can act through competitive inhibition of agr system such as S. aureus agr system via structure similarity to the AIPs [75]. Other S. aureus quorum-sensing inhibitors have been identified including linear peptidomimetics as competitive inhibitors to AgrC [76], savirin as potent inhibitor of AgrA [77] and the polyhydroxy anthraquinone ω-hydroxyemodin as inhibitor of AgrA [78].…”

Developments with investigating descriptors for antimicrobial AApeptides and their derivatives

“…In addition, rarely explored approaches including non-membrane-based mechanism of action, and immunomodulatory activities could provide alternative directions in the development of antimicrobial AApeptides. For example, antibacterial peptidomimetics targeting virulent gene expression is very scarce [16,17]. Antivirulent peptidomimetics that can potentially modulate the expression of virulence factors regulated by the accessory gene regulator ( agr ) system could be designed.…”

“…As such, HDPs display considerable selectivity toward bacteria instead of mammalian cells. In addition to targeting bacterial membranes, HDPs could have other mechanisms of action including targeting multiple bacterial proteins and nucleic acids, and inhibition of bacterial cellular pathways and gene expression [15–17]. The diverse cellular and membrane targets of HDPs have made a widespread of bacterial resistance less possible[15].…”