SENL101

Superantigens (SAgs) are extremely potent bacterial toxins, which evoke a virulent immune response, inducing nonspecific T-cell proliferation, rapid cytokine release, and lethal toxic shock, for which there is no effective treatment. We previously developed a small molecule, S101, which potently inhibits proliferating T cells. In a severe mouse model of toxic shock, a single injection of S101 given together with superantigen challenge rescued 100% of the mice. Even when given 2 hours after challenge, S101 rescued 40% of the mice. S101 targets the T-cell receptor, inflammatory response, and actin cytoskeleton pathways. S101 inhibits the aryl hydrocarbon receptor, a ligand-activated transcription factor that is involved in the differentiation of T-helper cells, especially Th17, and regulatory T cells. Our results provide the rationale for developing S101 to treat superantigen-induced toxic shock and other pathologies characterized by T-cell activation and proliferation.

Disinfectants, such as benzalkonium chloride (BAC), are commonly used to control Listeria monocytogenes and other pathogens in food processing plants. Prior studies have demonstrated that the resistance to BAC of L. monocytogenes was associated with the prolonged survival of three strains of molecular serotype 1/2a in an Iberian pork processing plant. Because survival in such environments is related to biofilm formation, we hypothesised that the influence of BAC on the biofilm formation potential of L. monocytogenes might differ between BAC-resistant strains (BAC-R, MIC≥10mg/L) and BAC-sensitive strains (BAC-S, MIC≤2.5mg/L). To evaluate this possibility, three BAC-R strains and eight BAC-S strains, which represented all of the molecular serotype 1/2a strains detected in the sampled plant, were compared. Biofilm production was measured using the crystal violet staining method in 96-well microtitre plates. The BAC-R strains produced significantly (p<0.05) less biofilm than the BAC-S in the absence of BAC, independent of the rate of planktonic growth. In contrast, when the biofilm values were measured in the presence of BAC, one BAC-R strain (S10-1) was able to form biofilm at 5mg/L of BAC, which prevented biofilm formation among the rest of the strains. A genetic determinant of BAC resistance recently described in L. monocytogenes (Tn6188) was detected in S10-1. When a BAC-S strain and its spontaneous mutant BAC-R derivative were compared, resistance to BAC led to biofilm formation at 5mg/L of BAC and to a significant (p<0.05) stimulation of biofilm formation at 1.25mg/L of BAC, which significantly (p<0.05) reduced the biofilm level in the parent BAC-S strain. Our results suggest that the effect of subminimal inhibitory concentrations of BAC on biofilm production by L. monocytogenes might differ between strains with different MICs and even between resistant strains with similar MICs but different genetic determinants of BAC resistance. For BAC-R strains similar to S10-1, subminimal inhibitory BAC may represent an advantage, compensating for the weak biofilm formation level that might be associated with resistance. Biofilm formation in the presence of increased subminimal inhibitory concentrations of the disinfectant may represent an important attribute among certain resistant and persistent strains of L. monocytogenes.