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.

Staphylococcus aureus Toxins: An Update on Their Pathogenic Properties and Potential Treatments

“…For instance, attempts to neutralize the α-hemolysin toxin during the course of human infection are underway and are based on substantial evidence for its participation in pathogenesis in murine models, as well as its putative importance in human disease. MEDI4893 (suvratoxumab), an α-hemolysin-neutralizing monoclonal antibody (mAb) formerly called LC10, is among the best-studied anti-virulence treatments against S. aureus infections [21]. As described above, α-hemolysin interacts with the metallopro-tease ADAM10, which promotes oligomerization and pore formation [98].…”

“…However, these studies have not yet generated promising results due to toxicity and/or low bioavailability. New options are now under study with a focus on biological molecules or compounds to interfere with toxins or toxin-regulator genes, constituting a new generation of promising antistaphylococcal treatments [17][18][19][20][21].…”

Oleate Hydratase (OhyA) Is a Virulence Determinant in Staphylococcus aureus

“…Evidence is accumulating that OhyA-derived h FA function to suppress cytokine production and inflammation to create a more tolerant environment for the commensal bacteria ( 2 – 5 ). Staphylococcus aureus is an important pathogen that deploys an array of virulence factors that engage host immune defenses to promote pathogenesis ( 6 – 8 ). S. aureus expresses an OhyA that catalyzes water addition to cis -9 double bonds ( 9 ) and protects against palmitoleic acid (16:1) ( 10 ), an antimicrobial fatty acid produced by the innate immune system ( 11 – 13 ).…”

Streptococcus pyogenes (“Group A Streptococcus”), a Highly Adapted Human Pathogen—Potential Implications of Its Virulence Regulation for Epidemiology and Disease Management

“…This review focuses on established virulence factors of GAS and their regulation, which play a major role in the different diseases caused by this versatile pathogen. In view of the—partially justified—reserve to treat every URT infection with an antibiotic, and the threat of antibiotic resistances developing even in GAS, deeper knowledge about the determinants of virulence may help to develop new “anti-virulence” agents for successful “antibiotic-free” treatments [ 34 , 35 ], or to be used as adjunct therapeutics in severe invasive GAS infections, as proposed recently for combination therapy of Staphylococcus aureus infections [ 36 ]. Other non-antibiotic antimicrobial agents directed against streptococcal constituents, which are not (yet) established as virulence regulators, might also be developed.…”