title: NVC-422 inactivates Staphylococcus aureus toxins.
abstract: Bacterial pathogens have specific virulence factors (e.g., toxins) that contribute significantly to the virulence and infectivity of microorganisms within the human hosts. Virulence factors are molecules expressed by pathogens that enable colonization, immunoevasion, and immunosuppression, obtaining nutrients from the host or gaining entry into host cells. They can cause pathogenesis by inhibiting or stimulating certain host functions. For example, in systemic Staphylococcus aureus infections, virulence factors such as toxic shock syndrome toxin 1 (TSST-1), staphylococcal enterotoxin A (SEA), and staphylococcal enterotoxin B (SEB) cause sepsis or toxic shock by uncontrolled stimulation of T lymphocytes and by triggering a cytokine storm. In vitro, these superantigens stimulate the proliferation of human peripheral blood mononuclear cells (PBMC) and the release of many cytokines. NVC-422 (N,N-dichloro-2,2-dimethyltaurine) is a broad-spectrum, fast-acting topical anti-infective agent against microbial pathogens, including antibiotic-resistant microbes. Using mass spectrometry, we demonstrate here that NVC-422 oxidizes methionine residues of TSST-1, SEA, SEB, and exfoliative toxin A (ETA). Exposure of virulence factors to 0.1% NVC-422 for 1 h prevented TSST-1-, SEA-, SEB-, and ETA-induced cell proliferation and cytokine release. Moreover, NVC-422 also delayed and reduced the protein A- and clumping factor-associated agglutination of S. aureus cultures. These results show that, in addition to its well-described direct microbicidal activity, NVC-422 can inactivate S. aureus virulence factors through rapid oxidation of methionines.
authors.affiliation: NovaBay Pharmaceuticals, Inc, Emeryville, California, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jekle
authors.forename: Jungjoo
authors.initials: J
authors.lastname: Yoon
authors.forename: Meghan
authors.initials: M
authors.lastname: Zuck
authors.forename: Ramin
authors.initials: R
authors.lastname: Najafi
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Timothy
authors.initials: T
authors.lastname: Shiau
authors.forename: Charles
authors.initials: C
authors.lastname: Francavilla
authors.forename: Suriani Abdul
authors.initials: SA
authors.lastname: Rani
authors.forename: Christian
authors.initials: C
authors.lastname: Eitzinger
authors.forename: Markus
authors.initials: M
authors.lastname: Nagl
authors.forename: Mark
authors.initials: M
authors.lastname: Anderson
authors.forename: Dmitri
authors.initials: D
authors.lastname: Debabov
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004768:Enterotoxins / Q000378:metabolism; D005083:Exfoliatins / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013205:Staphylococcal Protein A / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects*; D018089:Superantigens / Q000378:metabolism; D013654:Taurine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D001427:Bacterial Toxins; D016207:Cytokines; D004768:Enterotoxins; D005083:Exfoliatins; D013205:Staphylococcal Protein A; D018089:Superantigens; C030107:enterotoxin F, Staphylococcal; D013654:Taurine; C026066:enterotoxin A, Staphylococcal; C031818:enterotoxin B, staphylococcal; D008715:Methionine; C560851:NVC-422