Abstract
Staphylococcus aureus infections are becoming increasingly difficult to treat due to antibiotic resistance with the community-associated methicillin-resistant S. aureus (CA-MRSA) strains such as USA300 being of particular concern. The inhibition of bacterial virulence has been proposed as an alternative approach to treat multi-drug resistant pathogens. One interesting anti-virulence target is the agr quorum-sensing system, which regulates virulence of CA-MRSA in response to agr-encoded autoinducing peptides. Agr regulation confines exotoxin production to the stationary growth phase with concomitant repression of surface-expressed adhesins. Solonamide B, a non-ribosomal depsipeptide of marine bacterial origin, was recently identified as a putative anti-virulence compound that markedly reduced expression of α-hemolysin and phenol-soluble modulins. To further strengthen solonamide anti-virulence candidacy, we report the chemical synthesis of solonamide analogues, investigation of structure–function relationships, and assessment of their potential to modulate immune cell functions. We found that structural differences between solonamide analogues confer significant differences in interference with agr, while immune cell activity and integrity is generally not affected. Furthermore, treatment of S. aureus with selected solonamides was found to only marginally influence the interaction with fibronectin and biofilm formation, thus addressing the concern that application of compounds inducing an agr-negative state may have adverse interactions with host factors in favor of host colonization.
Highlights
Staphylococcus aureus is a colonizer of the human nasal cavity and skin in around 20–30% of the healthy human population and yet, it is a notorious opportunistic pathogen, causing severePLOS ONE | DOI:10.1371/journal.pone.0145618 January 5, 2016Solonamides Alter Immune Responses to S. aureus community-associated and nosocomial infections [1,2]
The ability of synthetic solonamides and lactam analogues to repress agr activity was examined by an agar diffusion assay [20] where reporter strains containing the lacZ reporter fused to S. aureus virulence genes hla, spa and the agr response regulator gene rnaIII were used to measure virulence gene regulation
We found that the amounts of cytokines secreted by dendritic cell (DC) in response to S. aureus treated with the agr inhibitors were significantly lower than those measured with untreated or DMSO treated S. aureus controls (Fig 6A)
Summary
Staphylococcus aureus is a colonizer of the human nasal cavity and skin in around 20–30% of the healthy human population and yet, it is a notorious opportunistic pathogen, causing severePLOS ONE | DOI:10.1371/journal.pone.0145618 January 5, 2016Solonamides Alter Immune Responses to S. aureus community-associated and nosocomial infections [1,2]. Two novel cyclodepsipeptides, named solonamide A (1) and B (2), were isolated from a marine bacterium (Photobacterium spp. strain S2753) with structures remarkably similar to those of the AIPs [9,10] They competitively inhibit agr by interfering with the binding of AIPs to the agr sensor kinase, AgrC [10]. Interference with bacterial virulence and/or cell-to-cell signaling pathways by solonamides may be a useful strategy for therapy against S. aureus infections Such anti-virulence approaches will inherently exert less selective pressure towards development of bacterial resistance as compared to antibiotics, and importantly they rely on a robust host immune response for the ultimate clearance of the infection [11]. We addressed the concern that these anti-virulence compounds might influence factors that promote host colonization, or have adverse effects on host immune responses
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