Antivirulence Strategies for the Treatment of Staphylococcus aureus Infections: A Mini Review

Abstract

Staphylococcus aureus is a Gram-positive bacterium capable of infecting nearly all host tissues, causing severe morbidity and mortality. Widespread antimicrobial resistance has emerged among S. aureus clinical isolates, which are now the most frequent causes of nosocomial infection among drug-resistant pathogens. S. aureus produces an array of virulence factors that enhance in vivo fitness by liberating nutrients from the host or evading host immune responses. Staphylococcal virulence factors have been identified as viable therapeutic targets for treatment, as they contribute to disease pathogenesis, tissue injury, and treatment failure. Antivirulence strategies, or treatments targeting virulence without direct toxicity to the inciting pathogen, show promise as an adjunctive therapy to traditional antimicrobials. This Mini Review examines recent research on S. aureus antivirulence strategies, with an emphasis on translational studies. While many different virulence factors have been investigated as therapeutic targets, this review focuses on strategies targeting three virulence categories: pore-forming toxins, immune evasion mechanisms, and the S. aureus quorum sensing system. These major areas of S. aureus antivirulence research demonstrate broad principles that may apply to other human pathogens. Finally, challenges of antivirulence research are outlined including the potential for resistance, the need to investigate multiple infection models, and the importance of studying antivirulence in conjunction with traditional antimicrobial treatments.

Keywords: Staphylococcus aureus – bacteria; accessory gene regulator; antimicrobial resistance; antivirulence; infection; quorum sensing; toxin; virulence.

FIGURE 1

Staphylococcus aureus virulence pathways and antivirulence strategies. (A) At top left, B-cells secrete antibodies against S. aureus antigens, the Fc region of which may be bound by Staphylococcal protein A (SpA) on the S. aureus membrane, thereby subverting immune responses. SpA may also bind the Fab portion of V_H3 family B-cell receptors, causing SpA-induced clonal expansion and anergic collapse. Superantigen activity of SpA also influences antibody (Ab) production by narrowing the breadth of anti-staphylococcal antibodies from V_H3 family B-cells, creating a preference for poorly functioning anti-SpA clones. To inhibit SpA activity, therapeutic monoclonal antibodies (mAbs) raised against an attenuated SpA have been delivered parenterally. (B) mAbs can also inhibit pore-forming toxins (PFTs). PFTs and phenol-soluble modulins (PSMs) are cytolytic toxins regulated by the accessory gene regulator (agr) quorum sensing system. To diminish these toxins’ cytotoxicity, decoy sponges limit the activity of the PFTs by presenting a variety of decoy receptors on their surfaces. (C) Neutrophils use reactive oxygen species (ROS) to kill phagocytosed S. aureus. These ROS are inhibited by staphyloxanthin, which in turn can be inhibited by the drugs naftifine and NP16. At the image center, a schematic of the agr quorum sensing system is shown with color-coded protein labels. Beginning with transcription and translation of the agr operon, AgrB modifies and secretes AgrD to produce autoinducing peptide (AIP). Upon reaching quorum, AIP binds the receptor kinase, AgrC, which phosphorylates the response regulator, AgrA. AgrA activates the P2 and P3 promoters of the agr operon in a positive feedback loop and increases the production of many cytolytic virulence factors including PSMs and many PFTs. The Agr system may be targeted by several agents including ambuic acid (inhibition of AIP secretion), solonamide B (inhibition of AIP activation of AgrC), and savirin and diflunisal (inhibition of AgrC and AgrA downstream of AIP sensing).