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.

Community-Associated Methicillin-Resistant Staphylococcus aureus Clonal Complex 80 Type IV (CC80-MRSA-IV) Isolated from the Middle East: A Heterogeneous Expanding Clonal Lineage

“…TSST-1 is a superantigen that stimulates the release of large amounts of proinflammatory factors in human infection, has been associated with human toxic shock syndrome [55], and causes sepsis by uncontrolled stimulation of T lymphocytes triggering a cytokine storm [56]. TSST-1 element is carried on a pathogenicity island known now as Sapl1, carrying the tst and other virulence factors [57].…”

Bactericidal Activity of N -Chlorotaurine against Biofilm-Forming Bacteria Grown on Metal Disks

“…Adherence of bacteria to surfaces is mediated by proteins in S. aureus (16), S. epidermidis (2), and P. aeruginosa (17). Since NCT and analog substances recently have been shown to directly inactivate bacterial toxins (8,18), it seems likely that the detachment of biofilms by NCT is due to an impact on these adherence proteins via oxidation of thiols and aromatic and amino groups (4,5). To clarify the exact molecular sites of attack could be an interesting item in future studies.…”

Antibiotics in the clinical pipeline at the end of 2015

“…Auriclosene (28) was designed to be a more stable derivative of the naturally occurring oxidant N-dichlorotaurine [172][173][174][175] and also was recently shown to inactivate S. aureus toxins. 176 Lefamulin (29) (BC-3781) is a semi-synthetic pleuromutilin 177,178 derivative originally discovered by Nabriva Therapeutics AG (Vienna, Austria). Nabriva executed an Initial Public Offering of shares in September 2015, raising $92 m to progress lefamulin (29) into phase-III trials for CABP.…”